3,4-dihydro-2H-1-benzopyran derivatives

ABSTRACT

The invention relates to compounds of the formula ##STR1## wherein R 1  is hydrogen or lower alkyl; R 2  is hydrogen or halogen; R 3 , R 4  and R 5  are hydrogen, acyl or lower alkyl; R 6  and R 7 , independently, are hydrogen or lower alkyl; X is alkylene 3-7  ; and n is an integer of zero to four; provided that only one of R 3 , R 4  or R 5  can be acyl; 
     enantiomers thereof, and, when R 7  is hydrogen, salts thereof with pharmaceutically acceptable bases. 
     The compounds of formulas I and II are useful as agents for the treatment of allergic conditions.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 507,383, filed June 24, 1983, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" denotes a straight or branchedchain saturated hydrocarbon containing 1 to 7 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl,heptyl and the like. The term "halogen" denotes all the halogens, thatis, bromine, chlorine, fluorine and iodine. The term "acyl" denotes an"alkanoyl" group derived from an aliphatic carboxylic acid of 1 to 7carbon atoms, for example, formyl, acetyl, propionyl, and the like; andan "aroyl" group derived from an aromatic carboxylic acid, such asbenzoyl and the like. The term "alkylene" denotes a straight or branchedchain radical of 3 to 7 carbon atoms, for example, propylene,2-methylpropylene, butylene, pentamethylene, hexamethylene,heptamethylene and the like. The term "aryl" denotes phenyl or phenylbearing one or more substituents selected from the group consisting ofhalogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lowralkylamino and di-lower alkylamino. The term "aralkyl" denotes astraight or branched chain lower alkyl group in which one or more of thehydrogen atoms have been replaced by an aryl group, for example, benzyland the like.

The invention relates to compounds of the formula ##STR2## wherein R¹ ishydrogen or lower alkyl; R² is hydrogen or halogen; R³, R⁴ and R⁵ arehydrogen, acyl or lower alkyl; R⁶ and R⁷, independently, are hydrogen orlower alkyl; X is alkylene₃₋₇ ; and n is an integer of zero to four;provided that only one of R³, R⁴ or R⁵ can be acyl;

enantiomers thereof, and, when R⁷ is hydrogen, salts thereof withpharmaceutically acceptable bases.

A preferred group of compounds of the invention are those represented bythe formula ##STR3## wherein R^(1') is lower alkyl, R^(2') is hydrogen,R^(3") is acyl, R^(6') is hydrogen and R^(7") is hydrogen.

A more preferred group of compounds of the invention are those offormula I in which R¹ is lower alkyl; R² is hydrogen; R³ is acyl; R⁴,R⁵, R⁶ and R⁷ are hydrogen; X is alkylene of 3 to 5 carbon atoms.

A still more preferred group of compounds of the invention are those offormula I in which R¹ is propyl, R² is hydrogen, R³ is acetyl; R⁴, R⁵,R⁶ and R⁷ are hydrogen; X is alkylene of 3 to 5 carbon atoms.

Preferred compounds of formulas I and II are:

racemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid;

(S)-(+)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid;

racemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-methyl-8-propyl-2H-1-benzopyran-2-propanoicacid; and

racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid.

Exemplary of the compounds of formulas I and II are:

(R)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid;

(S)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid;

racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-butanoicacid;

racemic-8-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-7-acetyl-2H-1-benzopyran-2-carboxylicacid;

racemic-5-acetyl-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-propanoicacid;

racemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-butanoicacid;

racemic-6-propanoyl-7-[7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptyloxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-butanoicacid;

(R)-(-)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid; and the like.

The compounds of formula I of the invention can be prepared ashereinafter described in Reaction Schemes I and II which follow:

Reaction Scheme I ##STR4## wherein R¹, R², R³, R⁴, R⁵, R⁶, X and n areas previously described, R^(7') is lower alkyl, R^(7") is hydrogen andHAL is halogen.

In Reaction Scheme I, the reaction of a compound of formula A, which areknown compounds or can be prepared according to known procedures, with acompound of formula III to yield a compound of formula Ia is carried outunder anhydrous conditions in an inert solvent, for example, acetone,methylethyl ketone, diethyl ketone, dimethylformamide or the like, atthe reflux temperature of the reaction mixture, in dimethylformamide,preferably at a temperature in the range of from about 70° to about 100°C., and in the presence of an acid acceptor, for example, potassiumcarbonate or the like. The preferred solvent is a mixture of acetone anddimethylformamide. The resulting compound of formula Ia can be recoveredutilizing conventional methods, for example, crystallization,chromatography or the like.

A compound of formula Ia can be converted to a compound of formula Ib byhydrolysis which is carried out with an alkali metal hydroxide, forexample, lithium hydroxide, sodium hydroxide, potassium hydroxide or thelike, in a mixture of water and a water miscible solvent, for example,methanol, ethanol, tetrahydrofuran or the like, at a temperature in therange of from about room temperature to the reflux temperature. Theresulting compound of formula Ib can be recovered utilizing conventionalmethods, for example, crystallization, chromatography or the like.

Reaction Scheme II ##STR5## wherein R¹, R², R⁶, R^(7'), R^(7"), HAL, Xand n are as previously described, and R^(3'), R^(4') and R^(5') arehydrogen or lower alkyl.

In Reaction Scheme II, the reaction of a compound of formula IV, whichare known compounds or can be prepared according to known procedures,with a compound of formula V to yield a compound of formula Ia' iscarried out under anhydrous conditions in an inert solvent, for example,acetone, methylethyl ketone, diethyl ketone, dimethylformamide or thelike, at the reflux temperature of the reaction mixture, indimethylformamide, preferably at a temperature in the range of fromabout 70° to about 100° C., and in the presence of an acid acceptor, forexample, potassium carbonate or the like. The preferred solvent is amixture of acetone and dimethylformamide. The resulting compound offormula Ia' can be recovered utilizing conventional methods, forexample, crystallization, chromatography or the like.

A resulting compound of formula Ia' can be converted to a compound offormula Ib' by hydrolysis which is carried out with an alkali metalhydroxide, for example, sodium hydroxide, potassium hydroxide or thelike, in a mixture of water and a water miscible alcohol, for example,methanol, ethanol or the like, at a temperature in the range of fromabout room temperature to the reflux temperature. The resulting compoundof formula Ib' can be recovered utilizing conventional methods, forexample, crystallization, chromatography or the like.

The starting materials of formulas III and V utilized for thepreparation of the compounds of formula I can be prepared according toReaction Schemes III, IV, V, VI, VII, VIII, IX or X which follow:

Reaction Scheme III ##STR6## wherein R³, R⁴, R⁵, R⁶, R^(7'), X, HAL andn are as previously described.

In Reaction Scheme III, the reaction of a compound of formula VI, whichare known compounds or can be prepared according to known procedures,with a compound of formula V to yield a compound of formula III iscarried out in an inert organic solvent such as dimethylformamide,acetone, methyl ethyl ketone or the like, preferred isdimethylformamide, in the presence of a base, for example, an alkalimetal carbonate such as potassium carbonate, sodium carbonate or thelike, or an alkali metal hydride such as sodium hydride or the like, ata temperature in the range of about 20° C. to about 150° C., preferablyat room temperature. The resulting compound of formula III can berecovered utilizing conventional methods, for example, crystallization,extraction, chromatography or the like.

Reaction Scheme IV ##STR7## wherein R⁶, R^(7') and n are as previouslydescribed, R^(3'), R^(4') and R^(5') are hydrogen or lower alkyl, and R⁸is lower alkyl or aryl.

In Reaction Scheme IV, the reaction of an allyl halide, which are knowncompounds or can be prepared according to known procedures, is reactedwith a compound of formula V to yield a compound of formula VII in aninert organic solvent such as dimethylformamide, acetone, methylethylketone and the like, preferred is dimethylformamide, in the presence ofa base, for example, an alkali metal carbonate such as potassiumcarbonate, sodium carbonate or the like, or an alkali metal hydride suchas sodium hydride or the like, at a temperature in the range of fromabout 20° C. to about 150° C., preferably at room temperature. Theresulting compound of formula VII can be recovered utilizingconventional methods, for example, crystallization, extraction,chromatography or the like.

A compound of formula VII is converted to a compound of formula VIIIutilizing the usual conditions for the hydroboration of an olefin. Forexample, utilizing a hydride of the formula (Q)₂ BH wherein Q ishydrogen, lower alkyl or lower cycloalkyl, preferred is borane (BH₃),dicyclohexylborane or borane-dimethyl sulfide complex, in an inert ethersolvent, preferably tetrahydrofuran, at a temperature in the range offrom about 0° C. to about 100° C., preferably at room temperature. Theorganoborane intermediate which is formed is oxidized, preferably byutilizing alkaline hydrogen peroxide, or the like. The resultingcompound of formula VIII can be recovered utilizing conventionalmethods.

A compound of formula VIII is reacted with a sulfonyl chloride of theformula R⁸ SO₂ Cl, wherein R⁸ is alkyl or aryl, such as phenyl, to yieldthe compound of formula VIIIa utilizing conditions conventionally usedfor converting an alcohol to a sulfonate ester, the methanesulfonateester is preferred. For example, the sulfonation is carried out in aninert solvent, such as dichloromethane utilizing a sulfonating agentsuch as alkylsulfonyl chloride, preferably methanesulfonyl chloride inthe presence of a base, for example, tri-lower alkylamine, pyridine orthe like, preferably triethylamine, at a temperature in the range offrom about 0° C. to about 25° C., preferably at 0° C. The resultingcompound of formula VIIIa can be recovered utilizing conventionalmethods.

A compound of formula VIIIa is converted to a compound of formula IIIautilizing conditions conventionally used for transforming a sulfonateester to an iodide. For example, a compound of formula VIIIa is treatedwith an alkali metal iodide, for example, sodium iodide, lithium iodide,potassium iodide and the like, preferably sodium iodide, in a solvent,for example, a dialkyl ketone, such as ethyl methyl ketone, acetone andthe like, preferably acetone, at a temperature in the range of fromabout 20° C. to about 100° C., preferably at 20° C. The resultingcompound of formula IIIa can be recovered utilizing conventionalmethods.

Alternatively, a compound of formula VII is converted to a compound offormula IIIa under conditions conventionally utilized for converting aterminal olefin to a primary iodide by hydroboration and iodination. Forexample, the reaction can be carried out utilizing iodine and a hydrideof the formula (Q)₂ BH wherein Q is hydrogen, lower alkyl or lowercycloalkyl, preferred is dicyclohexylborane, in the presence of an inertether solvent such as tetrahydrofuran and a base, for example, an alkakimetal carboxylate, preferably sodium acetate, at a temperature in therange of from about 0° C. to about 20° C. The resulting compound offormula IIIa can be recovered utilizing conventional methods.

Reaction Scheme V ##STR8## wherein R^(3'), R^(4'), R^(5'), R⁶ and R^(7')are as previous described, and R⁹ is aralkyl.

In Reaction Scheme V, the reaction of a compound of formula IX with acompound of the formula (C₆ H₅)₃ P═CHCO₂ R^(7'), wherein R^(7') is loweralkyl, preferably ethyl, which are known compounds or can be preparedaccording to known procedures, to yield a compound of formula XI, iscarried out in an inert aromatic hydrocarbon solvent, preferablytoluene, at a temperature in the range of from about 20° C. to about150° C., preferably at about 110° C. The resulting compound of formulaXI can be recovered utilizing conventional methods.

A compound of formula XI can be converted to a compound of formula Va byany known method for catalytic hydrogenolysis. For example, by treatmentwith hydrogen in the presence of a catalyst such as palladium on carbon,in a solvent, for example, an alkanol such as ethanol, preferably atroom temperature and one atmosphere of pressure. The resulting compoundof formula Va can be recovered utilizing conventional methods.

Reaction Scheme VI ##STR9## wherein R^(3'), R^(4'), R^(5') and R^(7')are as previously described.

In Reaction Scheme VI, a compound of formula XII, which are knowncompounds or can be prepared according to known procedures, ishydrogenated to yield a compound of formula Vb. More particularly, thereaction is carried out with a catalyst, for example, palladium oncarbon, in a solvent such as a lower carboxylic acid, preferably aceticacid, at a temperature in the range of about 20° C. to about 150° C.,preferably at 25° C., and at an increased pressure, preferably at 50psi. The resulting compound of formula Vb can be recovered utilizingconventional methods.

Reaction Scheme VII ##STR10## wherein R^(3'), R^(4'), R^(5'), R⁶ andR^(7') are as previously described, and n' is 2, 3 or 4.

In Reaction Scheme VII, a compound of formula XIII, which are knowncompounds can be prepared according to known procedures, is reacted witha compound of formula XIV, which are known compounds or can be preparedaccording to known procedures, to yield a compound of formula XV in thepresence of a catalyst, for example, a cyclic secondary amine such aspyrrolidine, and an inert aromatic hydrocarbon, preferably toluene, at atemperature in the range of about 25° C. to about 150° C., preferably at110° C. The resulting compound of formula XV can be recovered utilizingconventional methods.

A compound of formula XV is reduced to a compound of formula Vcutilizing, for example, borane in the presence of a Lewis acid such asboron trifluoride, boron trichloride, aluminum trichloride and the like,preferred is boron trifluoride etherate, and an inert ether solvent, forexample, tetrahydrofuran, at a temperature in the range of about 0° C.to about 25° C., preferably at 0° C. The resulting compound of formulaVc can be recovered utilizing conventional methods.

Reaction Scheme VIII ##STR11## wherein R^(4'), R⁶, R^(7') and n are aspreviously described, and R¹⁰ is hydrogen or lower alkyl.

In Reaction Scheme VIII, a phenolic compound of formula XVIII isconverted to its acyl derivative of formula XIX utilizing any suitableacylating agent, for example, a lower acyl halide or anhydride,preferred is acetic anhydride, in a suitable base, for example,pyridine, a lower alkylamine or the like, preferred is pyridine, at atemperature in the range of from about 0° C. to about 150° C.,preferably at 25° C. The resulting compound of formula XIX can berecovered utilizing conventional methods, if desired.

A compound of formula XIX can be converted to a compound of formula Vdutilizing any conventional reaction conditions for effecting a Friesrearrangement of a phenyl acylate. For example, it can be carried out inthe presence of a Lewis acid catalyst, for example, aluminum chloride,stannic chloride, boron trifluoride or the like, boron trifluorideetherate is preferred, in a solvent, for example, a halogenatedhydrocarbon, lower alkanoic acid or the like, preferably in acetic acid,at a temperature in the range of from about 20° C. to about 150° C.,preferably at 120° C. The resulting compound of formula Vd can berecovered utilizing conventional methods.

Alternatively, a compound of formula XVIII can be converted to acompound of formula Vd under conventional conditions for effecting aFriedel-Crafts acylation of a phenol. For example, the acylation can becarried out utilizing a Lewis acid catalyst, such as, aluminum chloride,stannic chloride, boron trifluoride or the like, preferably gaseousboron trifluoride, and an acylating agent, for example, a lower acylhalide, lower acyl anhydride, lower alkanoic acid or the like,preferably in acetic acid, at a temperature in the range of from about20° C. to about 150° C., preferred is 80° C. The resulting compound offormula Vd can be recovered utilizing conventional methods.

Reaction Scheme IX ##STR12## wherein R^(3'), R^(4') and R^(5') are aspreviously described, R¹¹ is hydrogen or ar-lower alkyl, preferablybenzyl, and R¹² is lower alkyl.

In Reaction Scheme IX, a compound of formula XXI, which are knowncompounds or can be prepared according to known procedures, is treatedwith acrolein to yield a compound of formula XXII utilizing as acatalyst, for example, a strong mineral acid such as hydrochloric acid,sulfuric acid, aryl or alkylsulfonic acid such as paratoluenesulfonicacid, or the like, preferably concentrated sulfuric acid, in a solvent,for example, a lower alkanol such as ethanol, methanol or the like,preferably methanol, at a temperature in the range of from about 20° C.to about 200° C., preferably at 150° C. The resulting compound offormula XXII can be recovered utilizing conventional methods.

A compound of formula XXII is converted to a compound of formula IXautilizing as a catalyst a strong mineral acid such as dilutehydrochloric acid, sulfuric acid or aryl- or alkylsulfonic acid such aspara-toluenesulfonic acid, or the like, preferably dilute aqueoushydrochloric acid, in an organic solvent which is miscible with watersuch as acetone, methanol, ethanol, tetrahydrofuran, acetic acid or thelike, preferably acetone, at a temperature in the range of from about20° C. to about 150° C., preferably at 60° C.

Reaction Scheme X ##STR13## wherein R^(3'), R^(4'), R^(5'), R^(7') andR⁸ are as previously described.

In Reaction Scheme X, a compound of formula XXIII, which are knowncompounds or can be prepared according to known procedures, is reactedwith a compound of formula X, which are also known compounds or can beprepared according to known procedures, to yield a compound of formulaXXIV, in an inert organic ether solvent or aromatic hydrocarbon, forexample, tetrahydrofuran, dioxane, glyne, benzene, toluene, xylene orthe like, preferably toluene, at a temperature in the range of fromabout 20° C. to about 200° C., preferably at 110° C. The resultingcompound of formula XXIV can be recovered utilizing conventionalmethods.

A compound of formula XXIV can be hydrogenated to form a compound offormula XXV utilizing a conventional catalyst for the hydrogenation, forexample, palladium on carbon, platinum oxide, nickel, or the like,preferred is platinum oxide, in the presence of a solvent, for example,a lower alkanoic acid, ethyl acetate, or the like, preferably alkylacetate, at a temperature in the range of from about 20° C. to about a100° C., preferably 20° C., and at atmospheric pressure. The resultingcompound of formula XXV can be recovered utilizing conventional methods.

A compound of formula XXV can be converted to a compound of formula XXVIby saponification which is followed by lactonization. The saponificationcan be carried out utilizing an alkali metal hydroxide, preferablypotassium hydroxide, in a solvent, for example, a lower alcohol,preferably methanol, at a temperature in the range of from about 20° C.to about 100° C., preferably 65° C. The lactonization can be carriedout, for example, with a lower alkanoic anhydride, such as, aceticanhydride, which can also be used as the solvent, at a temperature inthe range of from about 20° C. to about 200° C., preferably at theboiling point of the acetic anhydride. The resulting compound of formulaXXVI can be recovered utilizing conventional methods.

A compound of formula XXVI can be converted to a compound of formula IXbutilizing a conventional reducing agent, for example, a di-lower alkylaluminum hydride, preferably diisobutylaluminum hydride, at atemperature in the range of from about -50° C. to about -100° C.,preferably -75° C. in an inert solvent, for example, an aromatichydrocarbon, chlorinated alkane, or lower alkane, preferablydichloromethane. The resulting compound of formula IXb can be recoveredutilizing conventional methods.

The compounds of formula II of the invention can be prepared ashereinafter described in Reaction Schemes XI and XII.

Reaction Scheme XI ##STR14## wherein R¹, R², R³, R⁴, R⁵ and X are aspreviously described, R^(7') is lower alkyl, R^(7") is hydrogen and HALis halogen.

In Reaction Scheme XI, the reaction of a compound of formula A, whichare known compounds or can be prepared according to known procedures,with a compound of formula XXX to yield a compound of formula IIa iscarried out under anhydrous conditions in an inert solvent, for example,acetone, methylethyl ketone, diethyl ketone, dimethylformamide or thelike, at the reflux temperature of the reaction mixture, indimethylformamide, preferably at a temperature in the range of fromabout 70° to about 100° C., and in the presence of an acid acceptor, forexample, potassium carbonate or the like. The preferred solvent is amixture of acetone and dimethylformamide. The resulting compound offormula IIa can be recovered utilizing conventional methods, forexample, crystallization, chromatography or the like.

A compound of formula IIa can be converted to a compound of formula IIbby hydrolysis which is carried out with an alkali metal hydroxide, forexample, lithium hydroxide, sodium hydroxide, potassium hydroxide or thelike, in a mixture of water and a water miscible solvent, for example,methanol, ethanol, tetrahydrofuran or the like, at a temperature in therange of from about room temperature to the reflux temperature. Theresulting compound of formula IIb can be recovered utilizingconventional methods, for example, crystallization, chromatography orthe like.

Reaction Scheme XII ##STR15## whereinR¹,R²,R^(3'),R^(4'),R^(5'),R^(7'),R^(7"),HAL and X are as previouslydescribed.

In Reaction Scheme XII, a compound of formula IV is reacted with acompound of formula XXXIa to yield a compound of formula IIa', which issubsequently converted to a compound of formula IIb', as hereinbeforedescribed in connection with Reaction Scheme II.

The starting materials of formulas XXX and XXXIa which are utilized inReaction Schemes XI and XII for the preparation of the compounds offormula II can be prepared according to Reaction Schemes XIII, XIV andXV.

Reaction Scheme XIII ##STR16## wherein R³,R⁴,R⁵,R^(7'),X and HAL are aspreviously described.

In Reaction Scheme XIII, the reaction of a compound of formula VI, whichare known compounds or can be prepared according to known procedures,with a compound of formula XXXI to yield a compound of formula XXX iscarried out in an inert organic solvent such as dimethylformamide,acetone, methyl ethyl ketone or the like, preferred isdimethylformamide, in the presence of a base, for example, an alkalimetal carbonate such as potassium carbonate, sodium carbonate or thelike, or an alkali metal hydride such as sodium hydride or the like, ata temperature in the range of about 20° C. to about 150° C., preferablyat room temperature. The resulting compound of formula XXX can berecovered utilizing conventional methods, for example, crystallization,extraction, chromatography or the like.

Reaction Scheme XIV ##STR17## wherein R^(3'),R^(4'),R^(5'),R^(7') and R⁸are as previously described.

In Reaction Scheme XIV, a compound of formula XXIII is reacted withacrylonitrile to yield a compound of formula XXVII. The reaction iscarried out in the presence of a catalyst, for example, an aromaticamine, such as, triethylamine, diazabicycloundecene,diazabicyclo(2.2.2)octane is preferred, at a temperature in the range ofabout 20° C. to about 100° C., preferably 80° C., without solvent. Theresulting compound of formula XXVII can be recovered utilizingconventional methods.

A compound of formula XXVII is converted to a compound of formula XXVIIIby saponification, for example, with an alkali metal hydroxide, such as,potassium hydroxide, in a solvent, such as a water miscible organicsolvent, for example, tetrahydrofuran, methanol, ethanol, or the like,preferably ethanol or tetrahydrofuran, at a temperature in the range ofabout 20° C. to about 100° C., preferably at 60° C. to 70° C. Theresulting compound of formula XXVIII can be recovered utilizingconventional methods.

The conversion of a compound of formula XXVIII to a compound of formulaXXIX can be carried out by an esterification utilizing a lower alkanolas a reagent and a solvent, for example, ethanol, at a temperature inthe range of about 20° C. to about 100° C., preferably at 78° C., in thepresence of a catalyst, for example, a strong acid, such as, sulfuricacid, para-toluenesulfonic acid, or the like, preferablyparatoluenesulfonic acid. The resulting compound of formula XXIX can berecovered utilizing conventional methods.

A compound of formula XXIX can be converted to a compound of formulaXXXIa by catalytic hydrogenation, for example, utilizing palladium on asupport, nickel, platinum, preferably palladium on carbon in thepresence of a solvent, for example, a lower alkanol, acetic acid, ethylacetate, or the like, preferably ethanol, at a temperature in the rangeof from about 20° C.-200° C., preferably at 20° C., to one atmosphere ofpressure. The resulting compound of formula XXXIa can be recoveredutilizing conventional methods.

Reaction Scheme XV ##STR18## wherein R^(4'),R^(7') and R¹⁰ are aspreviously described.

In Reaction Scheme XV, a compound of the formula XXXIb can be convertedto a compound of formula XXXIc directly or via compound XXXII asdescribed above in Reaction Scheme VIII for the conversion of XVIII toVd.

Reaction Scheme XVI ##STR19##

Wherein R^(4'),R⁶,R^(7') and R⁹ are as previously described, and Halo ishalogen.

In Reaction Scheme XVI, the reaction of a compound of formula XVIIIa,with a compound of formula (a) to yield a compound of formula XXXIII iscarried out under anhydrous conditions in an inert solvent, for example,acetone, methylethyl ketone, diethyl ketone, dimethylformamide or thelike, at the reflux temperature of the reaction mixture, preferably at atemperature in the range of from about 40° to about 100° C., and in thepresence of an acid acceptor, for example, potassium carbonate or thelike. The preferred solvent is acetone. The resulting compound offormula XXXIII can be recovered utilizing conventional methods, forexample, crystallization, chromatography or the like.

A compound of formula XXXIII can be converted to a compound of formulaXXXIV utilizing a conventional reducing agent, for example, a di-loweralkyl aluminum hydride, preferably diisobutylaluminum hydride, at atemperature in the range of from about -50° C. to about -100° C.,preferably -75° C. in a inert solvent, for example, an aromatichydrocarbon, chlorinated alkane, or lower alkane, preferably toluene.The resulting compound of formula XXXIV can be recovered utilizingconventional methods.

Reaction Scheme XVII ##STR20##

Wherein m is 0 or 1, and R^(4'),R⁶,R^(7') and R⁹ are as previouslydescribed.

In Reaction Scheme XVII, the reaction of a compound of formula XXXIVwith a compound of the formula (C₆ H₅)₃ P═CH(CH═CH)_(m) CO₂ R^(7'),wherein R^(7') is lower alkyl, preferably ethyl, and m is 0 or 1, whichare known compounds or can be prepared according to known procedures, toyield a compound of formula XXXVI, is carried out in an inert aromatichydrocarbon solvent, preferably toluene, at a temperature in the rangeof from about 20° C. to about 150° C., preferably at about 110° C. Theresulting compound of formula XXXVI can be recovered utilizingconventional methods.

A compound of formula XXXVI can be converted to a compound of formulaXVIIIb by any known method for catalytic hydrogenation. For example, bytreatment with hydrogen in the presence of a catalyst such as palladiumon carbon, in a solvent, for example, an alkanol such as ethanol orethyl acetate, preferably at room temperature and one atmosphere ofpressure. The resulting compound of formula XVIIIb can be recoveredutilizing conventional methods.

This invention also relates to the pharmaceutically acceptable salts ofthe 3,4-dihydro-2H-1-benzopyran derivatives of formulas I and II andtheir enantiomers, when R⁷ is hydrogen. Said salts can be prepared byreacting an acid of formula I or II or an enantiomer thereof with a basehaving a non-toxic, pharmacologically and pharmaceutically acceptablecation. In general, any base which will form a salt with a carboxylicacid and whose pharmacological properties will not cause an adversephysiological effect when ingested by a warm-blooded animal isconsidered as being within the scope of the invention. Suitable basesthus includes, for example, alkali metal and alkaline earth metalhydroxides or carbonates, such as, sodium hydroxide, potassiumhydroxide, calcium hydroxide, potassium carbonate and the like, ammonia,primary, secondary and tertiary amines, such as monoalkylamines,dialkylamines, trialkylamines, nitrogen containing heterocyclic amines,for example, piperidine, basic amino acids such as lysine, and the like.The pharmaceutically acceptable salts thus produced are the functionalequivalent of the corresponding 3,4-dihydro-2H-1-benzopyran acids offormula I and II and their enantiomers and one skilled in the art willappreciate that, to the extent that the salts of the invention areuseful in therapy, the variety of salts encompassed by this inventionare limited only by the criterion that the bases employed in forming thesalts be both non-toxic and physiologically acceptable.

The useful antiallergic activity of the compounds of formulas I and II,and enantiomers thereof is demonstrated in vitro and in warm-bloodedanimals utilizing standard pharmacological procedures. Exemplary of suchprocedures are:

(a) Guinea Pig Ileum, In Vitro:

The guinea pig ileum bioassay system has been described by OrangeAusten, Adv. Immunol. 10: 105-144 (1969). A 1.5 cm segment is removedfrom animals weighing 300-400 g and suspended in an organ bathcontaining 10 ml of Tyrodes solution with 10⁻⁶ M atropine sulfate and10⁻⁶ M pyrilamine maleate. The bath is maintained at 37° C. and aeratedwith a mixture of 95% oxygen and 5% carbon dioxide. The SRS-A utilizedin this screen is obtained by challenging chopped lung fragments fromactively sensitized guinea pigs with egg albumin, in vitro. Adose-response curve to SRS-A challenge is established for the ileum. Thedose of SRS-A which gives 50% of the maximal contraction (EC₅₀) is thenused for subsequent challenge. The drug concentration which inhibits, by50%, the SRS-A-induced constriction of the guinea pig ileum isdetermined. In this bioassay system, the standard SRS-A antagonist,7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, has an IC₅₀ of 3.5×10⁻⁸ M.

(b) Guinea Pig Bronchoconstriction, In Vivo (Aerosol):

Male guinea pigs (Hartley strain) weighing 300 to 500 g are anesthetizedwith urethane (2 g/kg) intraperitoneally and a polyethylene cannula isinserted into the jugular vein for drug administration. Trachealpressure is recorded from a cannula inserted in the trachea andconnected to a Statham pressure transducer. After surgical preparationof the animals, a period of time is allowed for pulmonary functions tostabilize. The test compound is administered according to the followingprotocol. Propanolol (0.1 mg/kg) is administered intravenously while theanimals breathed spontaneously. Five minutes thereafter, the animals areexposed for a five minute period to a 1% (w/v) aerosol solution of testcompound (adjusted to an alkaline pH where necessary for drugsolubilization) or to distilled water of the appropriate pH (for controlpurposes). A Monaghan (Model 750) ultrasonic nebulizer is used toadminister all test compounds by inhalation. The nebulizer ultrasonicfrequency is adjusted to produce particles in the 1-8μ diameter range(average 3μ). Aqueous solutions are prepared freshly and introduced intothe chamber of the nebulizer. The output of the nebulizer is madeavailable to the animal by directing a bias flow of aerosol through a Ytube connected to the tracheal cannula. At the end of the exposureperiod, the animals are paralyzed with succinylcholine (1.2 mg/kg, i.v.)and mechanically respirated (Harvard rodent respirator) at 40breaths/minute and 2.5 cc tidal volume. Animals are then challenged witha maximum constrictory dose of leukotriene E₄ delivered intravenously 30seconds after administration of the succinylcholine.

The change (cm H₂ O) between pre and peak ventilatory pressure readingsaveraged for three control animals and five drug treated animals. Thepercent inhibition is calculated from the following formula: ##EQU1##When various drug concentrations are tested, the percent inhibition ateach concentration is plotted as log concentration (abscissa) versuspercent inhibition (ordinate) and the IC₅₀ is determined from linearregression analysis.

When compounds of formulas I and II, as listed hereinafter in Table I,were utilized in the test procedures described above the result set outin Table I were obtained:

                                      TABLE I                                     __________________________________________________________________________    SRS-A ANTAGONISM                                                                                     In vitro                                                                              Guinea Pig Bronchocon-                                                Guinea Pig                                                                            striction In vivo                              Test Compound          ileum IC.sub.50 (M)                                                                   aerosol - IC.sub.50(%)                         __________________________________________________________________________    rac-6-[3-(4-Acetyl-3-hydroxy-                                                                        1 × 10.sup.-7                                                                   1.0                                            2-propylphenoxy)propoxy]-3,4-dihydro-                                         2,5,7,8-tetramethyl-2H--1-benzopyran-                                         2-carboxylic acid                                                             rac-7-[3-(4-Acetyl-3-hydroxy-                                                                        1 × 10.sup.-7                                                                   >1.0                                           2-propylphenoxy)propoxy]-3,4-                                                 dihydro-2-methyl-2H--1-benzopyran-                                            2-propanoic acid                                                              rac-6-[3-(4-Acetyl-3-hydroxy-2-                                                                      2 × 10.sup.-7                                                                   1.0                                            propylphenoxy)propoxy]-3,4-dihydro-2,5,                                       7,8-tetramethyl-2H--1-benzopyran-2-                                           acetic acid                                                                   rac-7-[3-(4-Acetyl-3-hydroxy-2-                                                                      5 × 10.sup.-7                                                                   0.71                                           propylphenoxy)propoxy]-3,4-dihydro-2-                                         methyl-8-propyl-3H--1-benzopyran-2-                                           propanoic acid                                                                rac-6-[3-(4-Acetyl-3-hydroxy-2-                                                                      1 × 10.sup.-7                                                                   0.20                                           propylphenoxy)propoxy]-3,4-dihydro-2-                                         methyl-2H--1-benzopyran-2-carboxylic acid                                     rac-6-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-                                                       5 × 10.sup.-7                                                                   >1.0                                           propoxy]-3,4-dihydro-2-methl-2H--1-                                           benzopyran-2-propanoic acid                                                   rac-6-Acetyl-7-[3(4-acetyl-3-hydroxy-2-                                                              8 × 10.sup.-8                                                                   0.12                                           propylphenoxy)propoxy-2-methyl-propyl-                                        2H--1-benzopyran-2-propanoic acid                                             rac-6-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-                                                       1 × 10.sup.-7                                                                   1.0                                            propoxy]-3,4-dihydro-5,7,8-trimethyl-2H--1-                                   benzopyran-2-carboxylic acid                                                  rac-7-[3-(4-Acetyl-3-hydroxy-2-                                                                      1 × 10.sup.-7                                                                   0.67                                           propylphenoxy)propoxy]-3,4-dihydro-2H--1-                                     benzopyran-2-acetic acid                                                      rac-6-[3-(4-Acetyl-3-hydroxy-2-                                                                      4 × 10.sup.-7                                                                   1.0                                            propylphenoxy)propoxy]-3,4-dihydro-2H--1-                                     benzopyran-2-acetic acid                                                      rac-6-[3-(4-Acetyl-3-hydroxy-2-                                                                      5 × 10.sup.-7                                                                   0.50                                           propylphenoxy)propoxy]-3,4-dihydro-2H--1-                                     benzopyran-2-carboxylic acid                                                  rac-7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-                                                       1 ×  10.sup.-7                                                                  0.20                                           propoxy]-3,4-dihydro-8-propyl-2H--                                            benzopyran-2-carboxylic acid                                                  rac-7-[3-(4-Acetyl-3-hydroxy-2-                                                                      6 × 10.sup.-8                                                                   0.14                                           propylphenoxy)propoxy]-3,4-dihydro-2H--                                       1-benzopyran-2-carboxylic acid                                                rac-7-[3-(4-Acetyl-3-hydroxy-2-                                                                      1 × 10.sup.-7                                                                   >1.0                                           propylphenoxy)propoxy]-3,4-dihydro-2H--1-                                     benzopyran-3-carboxylic acid                                                  rac-6-Acetyl-7-[3-(4-acetyl-3-hydroxy-2-                                                             1 × 10.sup.-7                                                                   0.20                                           propylphenoxy)propoxy]-3,4-dihydro-2H--1-                                     benzopyran-2-carboxylic acid                                                  rac-6-Acetyl-7-[3-(4-acetyl-3-hydroxy-2-                                                             1 × 10.sup.-7                                                                   0.38                                           propylphenoxy)propoxy]-3,4-dihydro-8-propyl-                                  2H--1-benzopyran-2-carboxylic acid                                            rac-7-Acetyl-6-[3-(4-acetyl-3-hydroxy-                                                               2 × 10.sup.-7                                                                   0.34                                           2-propylphenoxy)propoxy]-3,4-dihydro-                                         2H--1-benzopyran-2-carboxylic acid                                            rac-6-Acetyl-7-[5-(4-acetyl-3-hydroxy-                                                               6 × 10.sup.-8                                                                   0.052                                          2-propylphenoxy)pentyloxy]-3,4-dihydro-                                       2H--1-benzopyran-2-carboxylic acid                                            rac-6-Acetyl-7-[[7-(4-acetyl-3-hydroxy-2-                                                            1 × 10.sup.-6                                                                   1.0                                            propylphenoxy)heptyl]oxy]-3,4-dihydro-2H--1-                                  benzopyran-2-carboxylic acid                                                  rac-8-Acetyl-7-[3-(4-acetyl-3-hydroxy-                                                               3 × 10.sup.-7                                                                   0.59                                           2-propylphenoxy)propoxy]-3,4-dihydro-2H--1                                    benzopyran-2-carboxylic acid                                                  rac-7-Acetyl-6-[3-(4-acetyl-3-hydroxy-                                                               5 × 10.sup.-7                                                                   1.0                                            2-propylphenoxy)propoxy]-3,4-dihydro-2-                                       methyl-2H--1-benzopyran-2-carboxylic                                          acid                                                                          __________________________________________________________________________

When in the above aerosol assay procedure leukotriene E₄ was replacedwith leukotriene D₄,racemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid was found to exhibit an IC₅₀ value of 0.0056% in inhibitingbronchoconstriction;(R)-(-)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid was found to exhibit an IC₅₀ value of 0.018% of inhibitingbronchoconstriction; and(S)-(+)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid was found to exhibit an IC50 value of 0.0018% in inhibitingbronchoconstriction.

                                      TABLE I                                     __________________________________________________________________________    SRS A: Antagonism                                                                                          In Vitro Guinea Pig                              Test Compound                ileum IC.sub.50 (M)                              __________________________________________________________________________    rac-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-                                                   2 × 10.sup.-6                              3,4-dihydro-2H--1-benzopyran-2-carboxylic acid                                rac-6-acetyl-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-                                                   1 × 10.sup.-6                              3,4-dihydro-8-propyl-2H--1-benzopyran-2-carboxylic acid                       rac-6-acetyl-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-                                                   3 × 10.sup.-6                              3,4-dihydro-2H--1-benzopyran-2-carboxylic acid                                rac-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy) =                                                   5 × 10.sup.-7                              pentyloxy]-3,4-dihydro-8-propyl-2H--1-benzopyran-2-                           carboxylic acid                                                               rac-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-                                                   1 × 10.sup.-7                              3,4-dihydro-2,5,7,8-tetramethyl-2H--1-benzopyran-2-                           carboxylic acid                                                               rac-7-[5-(4-acetyl-3-hydrophenoxy)pentyloxy]-3,4-                                                          5 × 10.sup.-6                              dihydro-2H--1-benzopyran-2-carboxylic acid                                    rac-6-acetyl-7-[6-(4-acetyl-3-hydroxy-2-propylphenoxy) =                                                   3 × 10.sup.-6                              hexyloxy]-3,4-dihyro-2H--1-benzopyran-2-carboxylic acid                       rac-6-acetyl-7-[4-(4-acetyl-3-hydroxy-2-propylphenoxy) =                                                   2 × 10.sup.-6                              butoxy]-3,4-dihydro-2H--1-benzopyran-2-carboxylic acid                        rac-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy)-3,4-                                                        6 × 10.sup.-6                              dihydro-8-propyl-2H--1-benzopyran-2-carboxylic acid                           rac-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-                                                   8 × 10.sup.-7                              3,4-dihydro-8-propyl-2H--1-benzopyran-2-carboxylic acid                       (+)-( .sub.--R)--6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)                                                 5 × 10.sup.-7                              pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H--1-benzo-                       pyran-2-carboxylic acid                                                       (-)-( .sub.--S)--6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-                                      8 × 10.sup.-7                              3,4-dihydro-2,5,7,8-tetramethyl-2H--1-benzopyran-2-carboxylic                 acid                                                                          (S)--6-acetyl-7-[  5-(4-acetyl-3-hydroxy-2-propylphenoxy)                                                  6 × 10.sup.-8                              pentyloxy]-3,4-dihydro-2H--1-benzopyran-2-carboxylic acid                     (R)--6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-prophylphenoxy)                                                   1 × 10.sup.-7                              pentyloxy]-3,4-dihydro-2H--1-benzopyran-2-carboxylic acid                     __________________________________________________________________________

(c) Oral Testing of Leukotriene Antagonists

Male guinea pigs (Hartley strain, Charles River) weighing 400 to 600 gwere anesthetized with urethane (2 g/kg) intraperitoneally and apolyethylene cannula was inserted into the jugular vein for intravenousdrug administration. Tracheal pressure (cm water) was recorded from aStatham pressure transducer. After surgical preparation of the animals,a period of time was allowed for spontaneous breathing to stabilize.Since previous studies have demonstrated a potentiating effect ofpropanolol (0.1 mg/kg, i.v.) on bronchoconstriction induced withsynthetic leukotriene, propanolol was administered five minutes prior tochallenge with leukotriene. Two minutes later, spontaneous breathing wasarrested with succinylcholine chloride (1.2 mg/kg, i.v.) and the animalsventilated with a Harvard (Model #680) small animal respirator set at 40breaths per minute and 4.0 cc stroke volume. The animals were challengedwith a maximum constrictory does of either leukotriene C₄ or leukotrieneD₄ or leukotriene E₄ (25 ug/kg, i.v.) at 5 minutes. Control vehicle ortest drug (adjusted to an alkaline pH where necessary for drugsolubilization) was administered (10 mg/kg, p.o.) two hours prior tochallenge with leukotriene. In order to determine the ID₅₀ for a testdrug, the dose is varied from 10 mg/kg, p.o. to 100, 50, 30, 20, 5, 3and 1 mg/kg, p.o.

In order to determine oral duration of action, the time between exposureto test drug and challenge with leukotriene is varied.

In test procedure (c), of the compounds tesed by this oral procedure,racemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid exhibited 46±14% inhibition of leukotriene D₄ inducedbronchoconstriction when administered at 10 mg/kg by the oral route.

A compound of formula I or II, an enantiomer thereof or a salt thereof,when R⁷ is hydrogen, or a composition containing a therapeuticallyeffective amount of a compound of formula I or II, an enantiomer thereofor a salt thereof, when R⁷ is hydrogen, can be administered by methodswell known in the art. Thus, a compound of formula I or II, anenantiomer thereof or a salt thereof, when R⁷ is hydrogen, can beadministered either singly or with other pharmaceutical agents, forexample, antihistamines, mediator release inhibitors, methyl xanthines,beta agonists or antiasthmatic steroids such as prednisone andprednisolone, orally, parenterally, rectally, or by inhalation, forexample, in the form of an aerosol, micropulverized powder or nebulizedsolution. Presently, the most preferred route of administration for thecompounds of formula I or II is by inhalation, for example, as anaerosol, and particularly for use as an antiasthmatic agent. For oraladministration they can be administered in the form of tablets,capsules, for example, in admixture with talc, starch, milk sugar orother inert ingredients, that is, pharmaceutically acceptable carriers,or in the form of aqueous solutions, suspensions, elixirs or aqueousalcoholic solutions, for example, in admixture with sugar or othersweetening agents, flavoring agents, colorants, thickeners and otherconventional pharmaceutical excipients. For parenteral administration,they can be administered in solutions or suspension, for example, as anaqueous or peanut oil solution or suspension using excipients andcarriers conventional for this mode of administration. Foradministration as aerosols, they can be dissolved in a suitablepharmaceutically acceptable solvent, for example, ethyl alcohol orcombinations of miscible solvents, and mixed with a pharmaceuticallyacceptable propellant. Such aerosol compositions are packaged for use ina pressurized container fitted with an aerosol valve suitable forrelease of the pressurized composition. Preferably, the aerosol valve isa metered valve, that is one which on activation releases apredetermined effective dose of the aerosol composition.

In the practice of the invention, the dose of a compound of formula I orII, an enantiomer thereof, or a salt thereof, when R⁷ is hydrogen, to beadministered and the frequency of administration will be dependent onthe potency and duration of activity of the particular compound offormula I or II, an enantiomer or salt thereof to be administered and onthe route of administration, as well as the severity of the condition,age of the warm-blooded animal to be treated and the like. Doses of acompound of formula I or II, an enantiomer thereof or a salt thereof,when R⁷ is hydrogen, contemplated for use in the practice of theinvention are in the range of from about 25 to about 1000 mg per day,preferably about 25 to about 250 mg either as a single dose or individed doses per day.

Since the compounds of formulas I and II of the invention possess anasymmetric carbon atom, they are ordinarily obtained as racemicmixtures. The resolution of such racemates into the optically activeisomers can be carried out by known procedures. Some racemic mixturescan be precipitated as eutectics and can thereafter be separated.Chemical resolution is, however, preferred. By this method,diastereomers are formed from the racemic mixture of a compound offormula I or II, when R⁷ is hydrogen, with an optically active resolvingagent, for example, an optically active base, such asd-(+)-α-methylbenzylamine, which can be reacted with a carboxyl group.The formed diastereomers are separated by selective crystallization andconverted to the corresponding optical isomer. Thus, the inventioncovers the racemates of the compounds of formulas I and II, as well astheir optically active isomers (enantiomers).

Alternatively, resolution can be achieved by treatment of thecorresponding acid of an ester of formula V or XXX with an opticallyactive amine resolving agent such as (R)- or (S)-alphamethylbenzylamine, (R)- or (S)-alphanaphthylethyl amine, quinine,quinidine, ephedrine and the like, preferably (R)- or (S)-alphamethylbenzylamine. After separation of the diastereomeric salts asdescribed above, the optically active acid obtained is recovered by acidtreatment and converted, after conversion to the corresponding ester,into the corresponding optically active compound of formula I or II, asdescribed for the preparation of the racemic series.

In addition, resolution can be achieved by treatment of thecorresponding acid of an ester of formulas III, V, XXX or XXXI with anoptically active alcohol to produce a mixture of diastereomeric esterswhich can be separated by crystallization or chromatography.Representative optically active alcohol resolving agents are menthol,borneol, 2-octanol, 2,3-butanediol, and the like. The preferred mode ofresolution involves the mono-ester of 2R,3R-butanediol and acids derivedfrom esters of formulas III, V, XXX or XXXI. These esters can be formedusing conventional methods. The preferred method is conventional Fisheresterification using a strong acid catalyst. The preferred acid catalystis para-toluenesulfonic acid. The diastereomeric esters from the acidsof formulas III or XXX can be formed by alkylation of the correspondingdiastereomeric esters from formulas V or XXXI with a dihaloalkane offormula VI, using conventional techniques described above. The preferredchromatographic technique for achieving the resolution is highperformance liquid chromatography (HPLC). After separation, the resolveddiastereomeric esters from acids of formulas III and XXX are convertedinto the corresponding resolved acids of formulas Ib' and IIb' usingconventional techniques described above for the racemic compounds.

In the following examples, all reactions were carried out under an inertatmosphere (argon). The "usual work-up" or "processing in the usualmanner" involves three extractions with the specified solvent. Theorganic extracts were then combined, washed with water and brine, driedover anhydrous magnesium sulfate, filtered and concentrated under wateraspirator pressure. The residue was dried to constant weight at 40°-50°C./high vacuum. Column chromatography was carried out using silica gel0.063-0.2 mm.

The examples which follow also further describe the invention. Alltemperatures given are in degree centigrade almost otherwise stated.

EXAMPLE 1

A mixture of 30.4 g of 2',4'-dihydroxyacetophenone, 28.8 g of ethyllevulinate, 21.3 g of pyrrolidine, and 400 ml of toluene was stirred andrefluxed for 3 hours with removal of water by means of a Dean-Starktrap. The resulting mixture was cooled in an ice bath and treated with300 ml of 1.2N aqueous hydrochloric acid. After being stirred at roomtemperature for 45 minutes, the mixture was treated with ether and theaqueous layer was separated. The organic solution was washed with 1.2Nhydrochloric acid. The aqueous acidic solutions were combined andextracted twice with ether. The organic solutions were combined, washedwith water, saturated aqueous sodium bicarbonate and brine, then dried(magnesium sulfate), filtered and concentrated under reduced pressure.The residual red oil (42 g) was chromatographed on 400 g of silica gel.Elution with 9:1 toluene-ethyl acetate gave 32.3 g (58.1%) ofracemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoicacid ethyl ester as an orange, viscous oil.

EXAMPLE 2

To a stirred solution of 1.5 g ofracemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoicacid ethyl ester in 8 ml of dry tetrahydrofuran, with ice bath cooling,was added 1.4 ml of boron trifluoride etherate, over a period of 2minutes. The mixture was stirred at 0°-5° C. for 5 minutes whereupon 5.4ml of 1M borane in tetrahydrofuran was added. Stirring was continued at0°-5° C. for 2.5 hours then the mixture was decomposed by the additionof glacial acetic acid. Solvents were removed in vacuo then the residuewas dissolved in methylene chloride. The solution was washed with sodiumbicarbonate solution and brine, then dried, filtered and concentratedunder reduced pressure. The residual orange oil (1.4 g) waschromatographed on 50 g of silica gel. Elution with 4:1 hexane-ethylacetate afforded 0.9 g (63.1%) ofracemic-3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acidethyl ester as a colorless oil.

Analysis Calculated for C₁₅ H₂₀ O₄ : C, 68.16; H, 7.63. Found: C, 67.86;H, 7.60.

EXAMPLE 3

To a stirred slurry of 120 mg of 50% sodium hydride-mineral oildispersion in 0.5 ml of dry N,N-dimethylformamide was added a solutionof 292 mg ofracemic-3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acidethyl ester in 3 ml of dry N,N-dimethylformamide. The mixture wasstirred at room temperature for 25 minutes at which point a solution of364 mg of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone in 3 mlof dry N,N-dimethylformamide was added. After being stirred at roomtemperature for 21 hours, the mixture was treated with ether and dilutehydrochloric acid and worked-up with ether in the usual manner giving523 mg of an orange oil. This material was chromatographed on 50 g ofsilica gel. Elution with 19:1 toluene-ethyl acetate afforded 257 mg(46.5%) ofracemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a pale yellow oil.

Analysis Calculated for C₂₉ H₃₈ O₇ : C, 69.86; H, 7.68. Found: C, 69.65;H, 7.73.

EXAMPLE 4

To a mixture of 1.55 g of the ester from Example 3 and 35 ml of 1:1tetrahydrofuran-water was added 2.3 g of lithium hydroxide monohydrate,with stirring. The mixture was stirred at room temperature for 22 hoursthen diluted with water and extracted 3 times with ether (ether extractsdiscarded). The aqueous solution was acidified to pH 1 by the additionof saturated aqueous oxalic acid and worked-up with ether in the usualmanner. There was obtained 1.4 g (95.8%) ofracemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoicacid as a viscous yellow oil.

Analysis Calculated for C₂₇ H₃₄ O₇ ; C, 68.92, H, 7.28. Found: C, 68.62;H, 7.23.

EXAMPLE 5

A mixture of 3.88 g of 2',4'-dihydroxy-3'-n-propylacetophenone, 3.17 gof ethyl levulinate, 0.83 ml of pyrrolidine, and 20 ml of toluene wasstirred at room temperature for 1 hour then refluxed for 3 hours withwater removal using a Dean-Stark trap. The resulting dark red-brownmixture was cooled, treated with 25 ml of 1N hydrochloric acid, andstirred at room temperature for 30 minutes. Water was added and themixture was worked-up with ether in the usual manner giving 5.1 g of adark red oil. This material was chromatographed on 100 g of silica gel.Elution with 9:1 and 4:1 toluene-ethyl acetate afforded 2.9 g (45.3%) ofracemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-3-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester as a yellow oil.

Analysis Calculated for C₁₈ H₂₄ O₅ : C, 67.48; H, 7.55. Found: C, 67.31;H, 7.54.

EXAMPLE 6

Using the procedure of Example 2, 257 mg ofracemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester was reduced with borane.tetrahydrofuran and borontrifluoride etherate. There was obtained 195 mg ofracemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester as a pale yellow oil, after chromatographicpurification on silica gel.

Analysis Calculated for C₁₈ H₂₆ O₄ : C, 70.56; H, 8.55. Found: C, 70.01;H, 8.28.

EXAMPLE 7

To a stirred slurry of 108 mg of 50% sodium hydride-mineral oildispersion (prewashed with hexane) in 1 ml of anhydrousN,N-dimethylformamide was added a solution of 268 mg ofracemic-3,4-dihydro-7-hydroxy-2-methyl-3-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester in 3 ml of dry N,N-dimethylformamide at roomtemperature, over a 1 minute period. After being stirred for 30 minutesat room temperature, the mixture was treated dropwise with a solution of313 mg of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone in 3 mlof dry N,N-dimethylformamide. Sodium iodide (0.3 g) was added and themixture was stirred at room temperature for 2.5 hours before beingquenched with 1 ml of water. After 30 minutes, 0.3 g of lithiumhydroxide monohydrate and 1 ml of water were added and stirring wascontinued for 3 hours. The mixture was acidified to pH 1 with 1Nhydrochloric acid and worked-up with ether in the usual manner. Theorange oily product (0.7 g) was chromatographed on 50 g of silica gel.Elution with 4:1 toluene-ethyl acetate gave 310 mg (69.1%) ofracemic-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid as a viscous yellow oil after drying at 60° C. under high vacuum.

Analysis Calculated for C₃₀ H₄₀ O₇ : C, 70.29; H, 7.87. Found: C, 70.19;H, 7.99.

EXAMPLE 8

Using the procedure of Example 1, 15 g of 2',5'-dihydroxyacetophenonewas condensed with 14.2 g of ethyl levulinate and 12.3 ml ofpyrrolidine, in 200 ml of toluene. The crude product (20.5 g) waspurified by high pressure liquid chromatography (silica gel; 2:1hexane-ethyl acetate) giving 17.6 g (64.1%) ofracemic-3,4-dihydro-6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoicacid ethyl ester as a yellow oil.

Analysis Calculated for C₁₅ H₁₈ O₅ : C, 64.74; H, 6.52. Found: C, 64.28;H, 6.64.

EXAMPLE 9

To a solution of 8.25 g ofracemic-3,4-dihydro-6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoicacid ethyl ester in 50 ml of dry glyme was added 7.29 ml of borontrifluoride etherate dropwise with stirring and ice bath cooling. Afterbeing stirred at 0°-5° C. for 10 minutes, the mixture was treated with1.75 g of boranedimethylamine complex. Stirring was continued for 1 hourat room temperature at which point 5 ml of glacial acetic acid was addedand the solution was poured into cold water and worked-up with ether inthe usual manner (the combined organic extracts were additionally washedwith sodium bicarbonate solution). The crude product was found tocontain a substantial amount of the starting ketone and was resubjectedto the foregoing reduction procedure and work-up. There was obtained 8.1g of a yellow oil which was purified by preparative high pressure liquidchromatography (silica gel, 2:1 hexane-ethyl acetate) giving 5.8 g(74.1%) of racemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil.

EXAMPLE 10

Utilizing the procedure of Example 7, 0.695 g ofracemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acidethyl ester was alkylated with 0.939 g of4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone using sodiumhydride and sodium iodide in dry N,N-dimethylformamide. Aftersaponification (1.25 g of lithium hydroxide monohydrate), there wasobtained 1.4 g of crude acid. Column chromatography on silica gel (50 g)afforded 0.837 g (67%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoicacid as a colorless oil (eluted with 9:1 and 4:1 toluene-ethyl acetate).

Analysis Calculated for C₂₇ H₃₄ O₇ : C, 68.92; H, 7.28. Found: C, 68.36;H, 7.20.

EXAMPLE 11

The procedure of Example 7 was employed to alkylate 0.9 g of the ethylester ofracemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acidwith 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone (1.5 g),using sodium hydride (12.16 mmole), and sodium iodide (10 mmoles), inN,N-dimethylformamide. After saponification with lithium hydroxidemonohydrate (1.5 g), the crude acid product was purified bychromatography on silica gel. There was obtained 1.16 g (68.9%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylicacid as an off-white solid mp 108°-110.5° C.

Analysis Calculated for C₂₅ H₃₀ O₇ : C, 67.86; H, 6.83. Found: C, 67.92;H, 6.97.

EXAMPLE 12

A 365 mg portion of 50% sodium hydride-mineral oil dispersion was washedwith hexane and suspended in 32 ml of anhydrous N,N-dimethylformammide.To the stirred slurry was added 1 g ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-carboxylicacid methyl ester. After being stirred at room temperature for 45minutes, the mixture was treated dropwise with 3.2 ml (4.47 g) of allylbromide. Stirring was continued for 90 hours at room temperature atwhich point 3 ml of methanol was added. The mixture was poured intowater and worked-up with ether in the usual manner giving 1.8 g of anamber oil. This material was purified by column chromatogrpahy on silicagel and then preparative high pressure liquid chromatography (silicagel, 19:1 hexane-ethyl acetate). There was obtained 772 mg (67.2%) ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(2-propenyloxy)-2H-1-benzopyran-2-carboxylicacid methyl ester as a pale-yellow oil. This material was evaporativelydistilled, bp 105°-107° C. (bath temperature) (0.02 mm), giving an oilwhich crystallized on standing to a solid, mp 68°-70° C.

Analysis Calculated For C₁₈ H₂₄ O₄ : C, 71.03; H, 7.95. Found: C, 71.37;H, 7.90.

EXAMPLE 13

To a solution of 1.8 g ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(2-propenyloxy)-2H-1-benzopyran-2-carboxylicacid methyl ester in 36 ml of anhydrous tetrahydrofuran was added 1.98ml of borane-dimethyl sulfide with stirring and ice bath cooling. Thereaction mixture was stirred for 1.5 hours at 0°-5° C., then decomposedby the dropwise addition of 9 ml of water. After being stirred at 0°-5°C. for 10 minutes, the mixture was treated dropwise with 6.84 ml of 3Nsodium hydroxide followed by 2.2 ml of 30% hydrogen peroxide. Themixture was stirred at 5°-10° C. for 1 hour then acidified with 7 ml of3N hydrochloric acid. Work-up with ether in the usual manner gave 2 g ofan oil which was purified by preparative HPLC (silica gel, 1:1hexane-ethyl acetate). There was obtained 1.22 g (64%) ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester as acololess oil.

Analysis Calculated for C₁₈ H₂₆ O₅ : C, 67.06; H, 8.13. Found: C, 67.39;H, 8.19.

EXAMPLE 14

To a solution of 0.3 g ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2-carboxylicacid methyl ester in 5 ml of anhydrous methylene chloride and 0.33 ml oftriethylamine was added 0.17 ml of methanesulfonyl chloride. The mixturewas stirred at room temperature for 45 minutes then treated with 1Nsulfuric acid and worked-up with methylene chloride in the usual manner.There was obtained 0.461 g ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-methanesulfonyloxypropoxy)-2H-1-benzopyran-2-carboxylicacid methyl ester as an oil which was used without further purification.

EXAMPLE 15

A mixture of the crude methanesulfonate from Example 14 (about 0.932mmole), 595 mg of sodium iodide, and 5 ml of acetone was stirred at roomtemperature for 43.5 hours then treated with water and worked-up withether in the usual manner (the ether extracts were additionally washedwith dilute sodium bisulfite solution). The oily product (390 mg) waschromatographed on 20 g of silica gel. Elution with 19:1 and 9:1hexane-ethyl acetate afforded 306 mg (76.0%) ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-iodopropoxy)-2H-1-benzopyran-2-carboxylicacid methyl ester as a colorless oil. In another experiment, iodideprepared in this way crystallized to a solid, mp 73°-75.5° C.

EXAMPLE 16

A mixture of 0.137 g of 2',4'-dihydroxy-3'-n-propylacetophenone, 0.195 gof anhydrous potassium carbonate, and 3 ml of anhydrousN,N-dimethylformamide was stirred for 1 hour at room temperaure. Asolution of the iodide from Example 15 (0.306 g) in 5 ml ofN,N-dimethylformamide was added and the mixture was stirred for 30minutes at room temperature and at 60° C. for 31 hours. After beingcooled, the reaction mixture was treated with 1N hydrochloric acid andworked-up with ether in the usual manner. The oily product (0.406 g) waschromatographed on 20 g of silica gel. Elution with 4:1 hexane-ethylacetate gave 0.291 g (82.5%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a pale-yellow oil. In another experiment, materialprepared in this way crystallized and afforded a colorless solid mp121°-123° C. (from ethanol).

Analysis Calculated for C₂₉ H₃₈ O₇ : C, 69.86; H, 7.68. Found: C, 69.31;H, 7.67.

EXAMPLE 17

A solution of 0.246 g of the methyl ester from Example 16, and 0.227 gof sodium hydroxide in 8 ml of methanol and 2 ml of water was stirred atroom temperature for 1.5 hours then treated with 1N hydrochloric acidand worked-up with ether in the usual manner. The crude product wasredissolved in ether and the solution was washed with dilute sodiumbicarbonate solution. The aqueous alkaline phase was acidified with 2Nhydrochloric acid and worked-up with ether in the usual manner giving0.161 g (67.3%) of acid as a yellow oil which crystallized on standing.Recrystallization from benzene-hexane gaveracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid as a colorless solid, mp 137°-139° C.

Analysis Calculated for C₂₈ H₃₆ O₇ : C, 69.40; H, 7.49. Found: C, 69.28;H, 7.58.

EXAMPLE 18

Using the procedure of Example 12, 1.42 g ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-hydroxy-2H-1-benzopyran-2-aceticacid methyl ester was alkylated with allyl bromide (2.79 g) and sodiumhydride (5.58 mmole) in anhydrous N,N-dimethylformamide. There wasobtained 1.35 g (83.1%) ofracemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(2-propenyloxy)-2H-1-benzopyran-2-aceticacid methyl ester as a yellow oil, after column chromatographicpurification (silica gel, 9:1 hexane-ethyl acetate).

Analysis Calculated for C₁₉ H₂₆ O₄ : C, 71.67; H, 8.23. Found: C, 71.54;H, 8.25.

EXAMPLE 19

To a stirred, ice-cold solution of 1M borane in tetrahydrofuran (10 ml)was added, dropwise, a solution of 2 ml (1.64 g) of cyclohexene in 6 mlof dry tetrahydrofuran. The mixture was allowed to stir at 0°-5° C. for1.5 hours. To the resulting slurry of dicyclohexylborane was added,dropwise a solution of 1.59 g of the allyl ether from Example 18 in 4 mlof tetrahydrofuan. The mixture was stirred at 0°-5° C. for 1 hour and atroom temperature for 18 hours at which point 20 ml of 1M methanolicsodium acetate was added dropwise followed by 23.8 ml of 0.4M methanoliciodine. The resulting mixture was stirred at room temperature for 4hours whereupon 3.1 ml of aqueous sodium thiosulfate was added. Thereaction mixture was poured into water and worked-up with ether in heusual manner. Chromatography of the crude product (4.4 g) on 100 g ofsilica gel afforded 1.71 g (76.7%) ofracemic-3,4-dihydro-6-(3-iodopropoxy)-2,5,7,8-tetramethyl-2H-1-benzopyran-2-aceticacid methyl ester as an oil, eluted with 19:1 and 9:1 hexane-ethylacetate.

EXAMPLE 20

Using the procedure of Example 16, 328 mg of2',4'-dihydroxy-3'-n-propylacetophenone was alkylated with 756 mg of theiodide from Example 19, and anhydrous potassium carbonate (467 mg), inanhydrous N,N-dimethylformamide. There was obtained 0.789 g (91.1%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-aceticacid methyl ester as a yellow oil after column chromatography (silicagel, 4:1 hexane-ether).

EXAMPLE 21

A 0.669 g sample of the methyl ester from Example 20 was saponified withsodium hydroxide using the procedure described in Example 17. The crudeacid product was chromatographed on 30 g of silica gel. Elution with 2:1hexane-ethyl acetate afforded 0.386 g (59.6%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-aceticacid as a yellow glass.

Analysis Calculated for C₂₉ H₃₈ O₇ : C, 69.86; H, 7.68. Found: C, 69.63;H, 7.89.

EXAMPLE 22

To a stirred solution of 0.8 g ofracemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester in 8 ml of pyridine was added 0.37 ml of aceticanhydride. The solution was stirred at room temperature for 5 hours thenpoured into ice-water and worked up with ether in the usual manner (thecombined ether extracts were additionally washed with 1N hydrochloricacid and saturated sodium bicarbonate solutions). The oily product (1.0g) was chromatographed on 50 g of silica gel. Elution with 19:1toluene-ethyl acetate afforded 0.575 g (63.3%) ofracemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester as a pale-yellow oil.

Analysis Calculated for C₂₀ H₂₈ O₅ : C, 68.94; H, 8.10. Found: C, 68.73;H, 8.06.

EXAMPLE 23

To a stirred solution of 276 mg ofracemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester in 2 ml of glacial acetic acid was added 0.21 ml ofboron trifluoride etherate, at room temperature. The mixture was stirredat 105° C. for 24 hours then cooled and diluted with ether. The ethersolution was washed with water and brine and processed in the usualmanner given 298 mg of a yellow-brown oil. This material waschromatographed on 30 g of silica gel. Elution with 4:1 toluene-ethylacetate afforded 183 mg (72.1%) ofracemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid as an off-white solid, mp 154°-156° C.

Analysis Calculated for C₁₈ H₂₄ O₅ : C, 67.48; H, 7.55. Found: C, 67.17;H, 7.72.

EXAMPLE 24

A solution of 692 mg ofracemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid and 100 mg of p-toluenesulfonic acid monohydrate in 10 ml ofabsolute ethanol was stirred and refluxed for 17 hours. The resultingsolution was cooled and treated with a small amount of saturated sodiumbicarbonate then concentrated in vacuo to remove the ethanol. Theresidue was treated with ether and the ether solution was processed inthe usual manner given 752 mg of a yellow oil. This material waschromatographed on 50 g of silica gel. Elution with 4:1 toluene-ethylacetate provided 706 mg (92.9%) ofracemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester as a yellow oil.

Analysis Calculated for C₂₀ H₂₈ O₅ : C, 68.94; H, 8.10. Found: C, 68.86;H, 7.85.

EXAMPLE 25

A mixture of 263 mg ofracemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester, 222 mg of anhydrous potassium carbonate, 0.39 ml of1,3-dibromopropane, 6 ml of anhydrous acetone, and 3 ml of anhydrousN,N-dimethylformamide was stirred and refluxed for 16 hours. Anadditional 0.25 g of anhydrous potassium carbonate was added andstirring, and refluxing were continued for 25 hours. The mixture wascooled and volatile materials were removed first under water aspiratorpressure and then high vacuum. The residue was treated with ether andacetone and the solids were removed by filtration. Concentration of thefiltrate in vacuo afforded 359 mg ofracemic-6-acetyl-7-(3-bromopropoxy)-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester as an orange oil.

EXAMPLE 26

A mixture of 335 mg ofracemic-6-acetyl-7-(3-bromopropoxy)-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester, 143 mg of 2',4'-dihydroxy-3'-n-propylacetophenone, 217mg of anhydrous potassium carbonate, 6 ml of anhydrous acetone, and 3 mlof anhydrous N,N-dimethylformamide was stirred and refluxed for 17hours. An additional 100 mg of potassium carbonate was added andstirring, and refluxing were continued for 4 hours. After being cooledto room temperature, the mixture was cautiously acidified to pH 1 by theaddition of 1N hydrochloric acid. Water was added and the mixture wasworked-up with ether in the usual manner. The residue waschromatographed on 50 g of silica gel. Elution with 9:1 toluene-ethylacetate afforded 219 mg (52.6%) ofracemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid ethyl ester as a yellow oil.

EXAMPLE 27

A 191 mg sample of the product from Example 26 was saponified withlithium hydroxide monohydrate, (273 mg) in 5 ml of 3:2tetrahydrofuran-water, using the procedure described in Example 4. Aftercolumn chromatography on silica gel,racemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid was obtained as a yellow, viscous oil.

Analysis Calculated for C₃₂ H₄₂ O₈ : C, 69.29; H, 7.63. Found: C, 69.07;H, 7.79.

EXAMPLE 28

An 809 mg sample of the ethyl ester ofracemic-3,4-dihydro-6-hydroxy-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylicacid was alkylated with 1.2 g of4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone, 448 mg of 50%sodium hydride-mineral oil dispersion, and 1.2 g of sodium iodide inanhydrous dimethylformamide, using the procedure of Example 7. Aftersaponification (1.2 g of lithium hydroxide monohydrate), there wasobtained 1.6 g of crude, crystalline acid. The material waschromatographed on 50 g of silica gel. Elution with 4:1, 2:1, and 1:1toluene-ethyl acetate gave 1.2 g (83.2%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-5,7,8-trimethyl-2H-1-benzopyran-2-carboxylicacid as an off-white solid, mp 144°-147° C.

Analysis Calculated for C₂₇ H₃₄ O₇ : C, 68.92; H, 7.28. Found: C, 68.68;H, 7.02.

EXAMPLE 29

A mixture of 25 g of p-benzyloxyphenol, 20 ml of freshly distilledacrolein, 70 ml of methanol, and 0.5 ml of concentrated sulfuric acidwas heated at 150° C. in a pressure bottle, with stirring for 2 hours.The mixture was cooled and diluted with ether. The ethereal solution waswashed with water and saturated sodium bicarbonate solution andprocessed in the usual manner. The brown, oily residue (47.9 g) waschromatographed on 250 g of silica gel. Elution with toluene gave 23.1 gof an orange oil which was rechromatographed on 300 g of silica gel.Elution with 9:1 hexane-ethyl acetate afforded 12.8 g (37.9%) ofracemic-3,4-dihydro-2-methoxy-6-(phenylmethoxy)-2H-1-benzopyran as ayellow oil. This material was dissolved in 200 ml of acetone and 120 mlof 2N aqueous hydrochloric acid was added. The mixture was stirred andrefluxed for 2 hours, kept overnight at room temperature, and refluxedfor an additional 2 hours. After being cooled, the mixture wasconcentrated under aspirator pressure to remove most of the acetone. Theaqueous residue was worked-up with ether in the usual manner (thecombined ether extracts were additionally washed with saturated sodiumbicarbonate solution) giving 12.1 g of a pale-yellow solid. Thismaterial was chromatographed on 250 g of silica gel. Elution with 9:1and 4:1 toluene-ethyl acetate afforded 9.8 g (80.7%) ofracemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-ol as apale-yellow solid, mp 92.5°-95° C.

Analysis Calculated for C₁₆ H₁₆ O₃ : C, 74.98; H, 6.29. Found: C, 74.78;H, 6.41.

EXAMPLE 30

A solution of 1.8 g ofracemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-ol and 2.6 g of(carbethoxymethylene)triphenylphosphorane in 20 ml of toluene wasstirred and refluxed for 22 hours. The solution was cooled and placed ona column of 50 g of silica gel packed in toluene. Elution with tolueneand 19:1 toluene-ethyl acetate gave 1.7 g (74.2%) ofracemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-acetic acidethyl ester as a pale-yellow oil. This material was dissolved in 25 mlof absolute ethanol and the solution was stirred in the presence of 0.2g of 10% palladium on carbon, at room temperature, in an atmosphere ofhydrogen. After 1.5 hours, hydrogen uptake ceased and the catalyst wasremoved by filtration. The filtrate was concentrated in vacuo to give1.2 g (97.6%) of racemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-aceticacid ethyl ester as a pale-yellow oil.

EXAMPLE 31

A mixture of 1.2 g ofracemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester,1.8 g of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone, 1.6 gof anhydrous potassium carbonate, 30 ml of dry acetone, and 15 ml of drydimethylformamide was stirred and refluxed for 23 hours. An additional1.6 g of potassium carbonate was added and the mixture was stirred andrefluxed for an additional 2.5 hours. After being cooled, the mixturewas cautiously poured into 1N aqueous hydrochloric acid. Work-up withether in the usual manner (the combined ether extracts were additionallywashed with saturated aqueous sodium bicarbonate) gave 3.7 g of a brownoil which was chromatographed on 50 g of silica gel. Elution with 19:1toluene-ethyl acetate afforded 1.6 g of a pale-yellow oil. A solution ofthis ester and 3.0 g of lithium hydroxide monohydrate in 40 ml of 1:1tetrahydrofuran-water was stirred at room temperature for 23 hours. Theresulting solution was diluted with water and acidified to pH 1 with 2Nhydrochloric acid. Work-up with ether in the usual manner gave an oilwhich was chromatographed on 50 g of silica gel. Elution with 4:1, 2:1,and 1:1 toluene-ethyl acetate afforded 831 mg (37%) ofracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-aceticacid as a pale-yellow solid, mp 102.5°-105° C.

Analysis Calculated for C₂₅ H₃₀ O₇ : C, 67.86; H, 6.83. Found: C, 68.03;H, 6.75.

EXAMPLE 32

A mixture of 17.5 g of (carbethoxymethylene)triphenylphosphorane and11.4 g of 4-benzyloxy-2-hydroxybenzaldehyde in 200 ml of toluene wasstirred and refluxed for 1 hour. After evaporation of the solvent invacuo, a residue of 28.2 g was obtained which contained(4'-benzyloxy-2'-hydroxy)benzenepropenoic acid ethyl ester andtriphenylphosphine oxide. This material was dissolved in 300 ml of ethylacetate and hydrogenated at atmospheric pressure and room temperature inthe presence of 0.35 g of platinum oxide. The catalyst was removed byfiltration and the filtrate was concentrated in vacuo giving 28.1 g ofproduct containing (4'-benzyloxy-2'-hydroxy)benzenepropanoic acid ethylester. This material was treated with 100 ml of 5% methanolic potassiumhydroxide solution and the mixture was refluxed for 2 hours. Most of themethanol was removed by concentration in vacuo and the residue waspartitioned between ether and water. The ether layer was discarded. Theaqueous phase was acidified with 2N hydrochloric acid and worked-up with1:1 ether-tetrahydrofuran in the usual manner affording 9.8 g of(4'-benzyloxy-2'-hydroxy)benzenepropanoic acid. This material wasdissolved in 98 ml of acetic anhydride and the solution was refluxed for2 hours. After being cooled, the solution was treated with 100 ml ofmethanol and the solvents were removed by concentration in vacuo. Themethanol treatment and evaporation were repeated twice more and theresidue was purified by high pressure liquid chromatography on silicagel (eluting solvent system 4:1 hexane-ethyl acetate). There wasobtained 6.2 g (48.8%) of3,4-dihydro-7-(phenylmethoxy)-1-benzopyran-2-one as a solid.

EXAMPLE 23

To a stirred solution of 6.2 g of3,4-dihydro-7-(phenylmethoxy)-1-benzopyran-2-one in 80 ml ofdichloromethane was added dropwise 20 ml of diisobutylaluminum hydridesolution (25% in toluene), at -76° C. The reaction mixture was stirredat this temperature for 1 hour whereupon 5 ml of methanol was cautiouslyadded. The solution was poured into 25 ml of 1N sulfuric acid and themixture worked-up with ether in the usual manner (the combined organicextracts were additionally washed with saturated sodium bicarbonatesolution). The residue (5.9 g) was purified by high pressure liquidchromatography on silicagel (eluting solvent system 3:1 hexane-ethylacetate. This afforded 4.8 g (76.8%) ofracemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-ol as acolorless solid, mp 64°-65.5° C.

Analysis Calculated for C₁₆ H₁₆ O₃ : C, 74.98; H, 6.29. Found: C, 74.44;H, 6.38.

EXAMPLE 34

A 2.2 g sample ofracemic-3,4-dihydro-7-(phenylmethoxy)-2h-1-benzopyran-2-ol was condensedwith (carbethoxymethylene)triphenylphosphorane (3.2 g) using theprocedure of Example 30. There was obtained 2.6 g (92.8%) ofracemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-acetic acidethyl ester as a yellow oil, after column chromatographic purification.This material was hydrogenolyzed over 0.2 g of 10% palladium on carbonas described in Example 30. There was obtained 1.9 g ofracemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl esteras a pale-yellow oil.

EXAMPLE 35

A 0.9 g sample of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-aceticacid ethyl ester was alkylated with 3 g of4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone using theprocedure described in Example 31. The crude product (2.6 g) waschromatographed on 50 g of silica gel giving 1.2 g of the desired esteras a pale-yellow oil (eluted with 19:1 toluene-ethyl acetate). Thismaterial was saponified with 2.0 g of lithium hydroxide monohydrateusing the procedure described in Example 31. The crude acid (1.1 g) waschromatographed on 50 g of silica gel. Elution with 2:1 and 1:1toluene-ethyl acetate afforded 682 mg (40.5%) ofracemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-aceticacid as a pale-yellow solid, mp 107°-109.5° C.

Analysis Calculated for C₂₅ H₃₀ O₇ : C, 67.86; H, 6.83. Found: C, 68.07;H, 6.87.

EXAMPLE 36

A solution of 8.75 g of ethyl 6-hydroxychromone-2-carboxylate in 200 mlof acetic acid was hydrogenated in the presence of 2 g of 10% palladiumon charcoal at 50 psi and room temperature by shaking the suspensionover a period of 17 hours. The catalyst was filtered and the filtratewas evaporated under reduced pressure to give 7.85 g of crude material.Purification of this compound by high-performance liquid chromatography(solvent system, hexane-ethyl acetate 3:1) yielded 4.9 g (59%) of purecrystalline racemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylicacid ethyl ester. Recrystallization from ethyl-acetate-hexane gavecolorless solid, mp 72°-74° C.

Analysis Calculated for C₁₂ H₁₄ O₄ : C, 64.85; H, 6.35. Found: C, 64.57;H, 6.45.

EXAMPLE 37

Into a solution of 2.23 g of racemic-ethyl6-hydroxychroman-2-carboxylate in 30 ml of acetic acid was introduced astream of boron trifluoride gas at 20°-25° C. A cold water bath was usedduring the introduction of the gas (30-45 minutes) to control thetemperature of the exothermic reaction. The cold bath was removed andthe reaction mixture was heated at 80° C. for 5 hours; then the reactionmixture was cooled and carefully poured into a mixture of saturatedbicarbonate and ice, and the product was extracted with 1:1tetrahydrofuran-ether. The crude material obtained after evaporation ofthe solvent was chromatographed on a silica gel column to yield 1.6 g(60%) ofracemic-7-acetyl-6-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acidethyl ester as a viscous oil.

EXAMPLE 38

Using the procedure described in Example 42, 1.0 g of racemic-ethyl6-hydroxychroman-2-carboxylate was converted intoracemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid in 27.3% yield, as a white crystalline material, mp 125°-127° C.

Analysis Calculated for C₂₄ H₂₈ O₇ : C, 67.28; H, 6.59. Found: C, 67.27;H, 6.67.

EXAMPLE 39

A mixture of 1.6 g of racemic-7-acetyl-6-hydroxychroman-2-carboxylicacid ethyl ester, 3.0 g of potassium carbonate, 5 ml of1,3-dibromopropane, 60 ml of dry acetone and 30 ml of dry dimethylformamide was stirred and refluxed for 20 hours. After removal of mostof the solvents in vacuo, the residue was diluted with ether and treatedcautiously with 1N hydrochloric acid. The organic phase was separated,washed with saturated sodium bicarbonate solution and water, dried andconcentrated in vacuo. The crude bromopropyl derivative (2.1 g) wasdissolved in 30 ml of acetone and added to a mixture of 1.2 g of2',4'-dihydroxy-3'-propylacetophenone, 2.5 g of anhydrous potassiumcarbonate, 30 ml of dry acetone and 30 ml of dimethylformamide. Thereaction mixture was gently refluxed for 25 hours. After removal of mostof the solvent, the product was extracted with ether, the ether extractswashed with brine and dried. The crude material (3.1 g) obtained afterevaporation of the solvent was chromatograhed on silica gel to afford1.3 g (43%) of the desired ester. This material was hydrolyzed bytreating the ester (1.3 g) in 18 ml of tetrahydrofuran) with an aqueoussolution of lithium hydroxide (2.2 g of lithium hydroxide monohydrate in18 ml of water). The cloudy reaction mixture was stirred for 21 hours atroom temperature, poured into 1N hydrochloric acid and the productextracted with ether. The organic phase was washed with brine, dried andevaporated to give 1.2 g of a viscous yellow oil. Purification bychromatography on a silica gel column afforded 0.778 g (27.3%) ofracemic-7-acetyl-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid as a white crystalline material, mp 140.5°-142.5° C. (from ethylacetate)

Analysis Calculated for C₂₆ H₃₀ O₈ : C, 66.37; H, 6.43. Found: C, 66.44;H, 6.51.

EXAMPLE 40

Using the hydrogenation conditions described in Example 36, 1.09 g ofethyl 7-hydroxychromone-2carboxylate was converted into racemic-ethyl7-hydroxychroman-2-carboxylate in 53% yield as a crystalline material,mp 81°-82.5° C. (from ethyl acetate-hexane).

Analysis Calculated for C₁₂ H₁₄ O₄ 0 C, 64.85; H, 6.35. Found: C, 64.60;H, 6.26.

EXAMPLE 41

A 1.1 g sample of racemic ethyl 7-hydroxychroman-2-carboxylate wastreated with 10 ml of 1:1 acetic anhydride-pyridine and stirred for 17hours at room temperature. After removal of the solvents, the residualproduct (1.2 g) was dissolved in 12 ml of glacial acetic acid andtreated with 1.26 ml of borontrifluoride etherate. The reaction mixturewas gently refluxed for 17 hours, cooled, poured carefully into amixture of sodium bicarbonate and ice and the product extracted with 1:1tetrahydrofuran-ether. After evaporation of the solvent, 1.1 g of cruderacemic-7-hydroxy-6-acetylchroman-2-carboxylic acid was obtained.Conversion of this material into the corresponding ethyl ester wasachieved by refluxing 1.1 g of the crude acid in absolute ethanol in thepresence of 10 mg of p-toluenesulfonic acid for 17 hours. After removalof most of the solvent, the product was extracted with 1:1tetrahydrofuran-ether, washed with saturated sodium bicarbonatesolution, water, dried and the solvents concentrated to give 1.2 g ofcrude ethyl ester as a mixture of the 6-acetyl and 8-acetyl derivativesin a ratio of about 7:1. This material was purified by columnchromatography on silica gel to afford 0.7 g (53.5%) ofracemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acidethyl ester as a colorless crystalline material mp 93.5°-95.5° C. (fromethyl acetate-hexane).

EXAMPLE 42

A mixture of 1 g of racemic-ethyl 7-hydroxychroman-2-carboxylate, 1.6 gof 4'-(3-bromopropoxy)-2'-hydroxy-3'-propylacetophenone, 1.6 g ofanhydrous potassium carbonate, 25 ml of acetone and 12 ml ofdimethylformamide was stirred and refluxed for 23 hours. After cooling,1N hydrochloric acid was cautiously added and the product was extractedwith ether. The ether layer was washed with brine, dried, and evaporatedin vacuo to afford 3.6 g of an orange oil. Chromatographic purificationon silica gel yielded 1.4 g of the alkylated ethy ester. This material,dissolved in 20 ml of tetrahydrofuran, was treated with aqueous lithiumhydroxide (2.6 g of lithium hydroxide monohydrate in 20 ml of water) andstirred for 23 hours at room temperature. The reaction mixture wasacidified and the product extracted with ether, washed with brine anddried. Solvent removal gave 1.3 g of pale-yellow acid which was purifiedon a chromatographic column of silica gel to afford 0.554 g (28.7%) ofracemic-7-[3-(4-acetyl-3-hydroxy-2-propyl)phenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid as a white crystalline material mp 142.5°-145° C.

Analysis Calculated for C₂₄ H₂₈ O₇ : C, 67.28; H, 6.59. Found: C, 67.34;H, 6.62.

EXAMPLE 43

Using the procedure described in Example 39, 0.840 g of racemic-ethyl6-acetyl-7-hydroxychroman-2-carboxylate was converted intoracemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-2-benzopyran-2-carboxylicacid in 49.5% yield as a colorless solid mp 176°-178.5° C. (d) (fromethyl acetate).

Analysis Calculated for C₂₆ H₃₀ O₈ : C, 66.37; H, 6.43. Found: C, 66.27;H, 6.39.

EXAMPLE 44

Using the hydrogenation conditions described in Example 36, 5.52 g ofethyl 7-hydroxy-8-propylchromone-2-carboxylate was converted intoracemic-ethyl 7-hydroxy-8-propylchroman-2-carboxylate in 43.5% yield, asa viscous pale yellow oil.

EXAMPLE 45

Using the procedure described in Example 41, 1.3 g ofracemic-3,4-dihydro-7-hydroxy-8-propyl-2H-1-benzopyran-2-carboxylic acidethyl ester was converted into the corresponding 6-acetyl derivative in79.5% yield, as a vicous oil.

EXAMPLE 46

Using the procedure described in Example 42, 1.0 g ofracemic-7-hydroxy-8-propylchroman-2-carboxylic acid ethyl ester wasconverted intoracemic-7-[3-(4-acetyl-3-hydroxy-2-propyl)phenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid as a pale yellow solid, mp 105°-107° C.

Analysis Calculated for C₂₇ H₃₄ O₇ : C, 68.92; H, 7.28. Found: C, 69.06;H, 7.29.

EXAMPLE 47

A mixture of 0.85 g of racemic-ethyl6-acetyl-7-hydroxy-8-propylchroman-2-carboxylate, 1.2 g of anhydrouspotassium carbonate, 2.3 ml of 1,3-dibromopropane, 0.1 g of18-crown-6-ether and 20 ml of acetonitrile was refluxed for 23 hours.After cooling, the reaction mixture was diluted with ether. The organicphase was washed with brine, dried, and evaporated to afford 1.2 g ofthe bromopropyl derivative as a yellow oil. Using the conditionsdescribed in Example 39, this bromide was converted by alkylation of2',4'-dihydroxy-3'-propylacetophenone and subsequent saponification,intoracemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid in about 40% overall yield. This acid was obtained as a colorlesssolid, mp 108°-110.5° C. (from ethyl acetate-hexane).

Analysis Calculated for C₂₉ H₃₆ O₈ : C, 67.95; H, 7.08. Found: C, 68.16;H, 7.20.

EXAMPLE 48

Using the procedure described in Example 39, with the exception that1,5-dibromopentane was substituted for 1,3-dibromopropane,racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acidethyl ester was converted intoracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid in 32.8% yield, as a colorless solid, mp 113°-115° C. (from ethylacetatehexane).

Analysis Calculated for C₂₈ H₃₄ O₈ : C, 67.45; H, 6.87. Found: C, 67.61;H, 6.80.

EXAMPLE 49

Using the procedure described in Example 39, with the exception that1,7-dibromoheptane was substituted for 1,3-dibromopropane,racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acidethyl ester was converted intoracemic-6-acetyl-7-[7-(4-acetyl-3-hydroxy-2-propylphenoxy)heptyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid as a colorless solid, mp 133°-135° C. (from ethyl acetate-hexane),in 39.1% overall yield.

Analysis Calculated for C₃₀ H₃₈ O₈ : C, 68.42; H, 7.27. Found: C, 68.22;H, 7.18.

EXAMPLE 50

Using the procedure described in Example 39, 0.62 g ofracemic-8-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acidethyl ester was converted intoracemic-8-acetyl-7[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid in 27.7% overall yield, as a colorless solid, mp 146.5°-148.5° C.(from ethyl acetate-hexane).

Analysis Calculated for C₂₆ H₃₀ O₈ : C, 66.37; H, 6.43. Found: C, 66.51;H, 6.47.

EXAMPLE 51

A 0.125 g sample ofracemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acidethyl ester was converted intoracemic-3,4-dihydro-7-acetyl-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylicacid ethyl ester in 65.5% yield, as a viscous oil, using the proceduredescribed in Example 37.

EXAMPLE 52

A 96.5 mg sample ofracemic-3,4-dihydro-7-acetyl-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylicacid ethyl ester was converted intoracemic-7-acetyl-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylicacid in 65.7% yield as a foam, using the procedure described in Example39.

EXAMPLE 53

A mixture of 1.14 g of 4-benzyloxy-2-hydroxybenzaldehyde, 0.125 g of1,4-diazabicyclo[2,2,2]octane and 0.65 g of acrylonitrile was stirredand heated at 80°-85° C., under argon, for 2 hours. After removal of thesolvent, the residual product was dissolved intetrahydrofuran-ether(1:1), washed with 1N-sodium hydroxide, water,dried, and the solvents evaporated in vacuo. The crude material (1.10 g)was purified by column chromatography on silica gel to afford 0.6 g(45.7%) of 7-(phenylmethoxy)-2H-1-benzopyran-3-carbonitrile, as acolorless solid mp 95°-98° C. (from ethyl acetatehexane).

Analysis Calculated for C₁₇ H₁₃ NO₂ : C, 77.55; H, 4.98; N, 5.32. Found:C, 77.41; H, 5.00; N, 4.80.

EXAMPLE 54

A 2.2 g sample of 7-(phenylmethoxy)-2H-1-benzopyran-3-carbonitriledissolved in 40 ml of a mixture of tetrahydrofuran-ethyl alcohol (1:1)was treated with 20 ml of a 2N potassium hydroxide and the reactionmixture was refluxed under argon for 21 hours. An additional, 10 ml of2N potassium hydroxide was added and the mixture was stirred andrefluxed for an additional 27 hours. The reaction mixture was acidifiedwith 1N hydrochloric acid, extracted with ethyl acetate, washed withbrine, dried and the solvent evaporated in vacuo to afford 2.2 g of anorange solid. This material, dissolved in 30 ml of ethanol containing0.3 g of p-toluenesulfonic acid monohydrate, was refluxed for 18 hoursunder argon. after removal of most of the solvent, the residual productwas extracted with ether, the extract washed with saturated sodiumbicarbonate solution, water, dried and the solvent evaporated to afford2.3 g of crude ethyl ester. Purification by chromatography on a silicagel column afforded 1.4 g of7-(phenylmethoxy)-2H-1-benzopyran-3-carboxylic acid ethyl ester as acrystalline material.

EXAMPLE 55

The ester from Example 54 (1.4 g) was dissolved in 25 ml of absolutealcohol and hydrogenated at atmospheric pressure in the presence of 0.2g of 10% palladium on charcoal. The catalyst was removed by filtrationon diatomaceous earth and after removal of the solvent, 0.9 g ofracemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-3-carboxylic acid ethylester was obtained as a white solid.

EXAMPLE 56

The ethyl ester from Example 55 was converted into racemic7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid in 17.7% overall yield, using the procedures described in Example42. The acid was obtained as a colorless solid mp 153.5°-155.5° C. (fromethyl acetate-ether-hexane).

Analysis Calculated for C₂₄ H₂₈ O₇ : C, 67.28; H, 6.59. Found: C, 67.46;H, 6.66.

EXAMPLE 57

A 0.9 g sample ofracemic-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethylester dissolved in 5 ml of pyridine was treated with 1.2 ml of aceticanhydride. After being stirred for 3 hours at room temperature, thereaction mixture was diluted with ether. The organic layer was washedwith 2N hydrochloric acid, sodium bicarbonate, brine, dried and thesolvent evaporated. There was obtained 1.2 g of crude acetate which wasdissolved in 10 ml of glacial acetic acid and treated with 1 ml of borontrifluoride etherate. The reaction mixture was heated at 100° C. underargon for 6 hours. After cooling, ether was added. The organic layer waswashed several times with water, dried, and the solvent evaporated invacuo to afford 1.0 g of an orange oil. The esterification of thismaterial with ethanol was carried out as described in Example 41 givingracemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acidethyl ester.

EXAMPLE 58

Racemic-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acidethyl ester was converted intoracemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylicacid using the procedure described in Example 39. The acid product was acolorless solid, mp 127°-129° C. dec. (from ethyl acetate-hexane).

Analysis Calculated for C₂₆ H₃₀ O₈ : C, 6.43; H, 6.43. Found: C, 66.45;H. 6.43.

EXAMPLE 59

Using the procedure described in Example 41, 11.3 g ofracemic-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethylester was converted into cruderacemic-7-hydroxy-6-acetyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acidin 93% yield (11 g). A 1 g sample of this crude acid was treated with3.8 g of (-)-(2R,3R)-butanediol in 30 ml of toluene, in the presence of0.2 g of p-toluenesulfonic acid monohydrate. After 18 hours at reflux,the reaction mixture was cooled and poured into a saturated solution ofsodium bicarbonate and the product extracted with ether. The etherextract was washed twice water, dried and concentrated. There wasobtained 1.8 g of crude product after removal of the solvents which wasa mixture of the 6-acetyl and the 8-acetyl mono-butanediol esterderivatives in a ratio of about 7:1. Purification of this material byHPLC afforded 0.8 g (61%) of [2R,S-2-[(1R*,2R*)]]-6-acetyl-7-hydroxy-3,4-dihydroxy-2H-1-benzopyran-2-carboxylic acid1-methyl-2-hydroxypropylester, as a viscous pale yellow oil.

EXAMPLE 60

Using the procedure described in Example 25, 3.5 g of[2R,S-2-[(1R*,2R*)]]-6-acetyl-7-hydroxy-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 1-methyl-2-hydroxypropyl ester, 12 ml of 1,5-dibromopentane, 7.2. gof anhydrous potassium carbonate in 100 ml acetone and 50 ml ofN,N-dimethylformamide afforded 2.6 g (50%) of[2R,S-2-[(1R*,2R*)]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 2-hydroxy-1-methylpropyl ester. This material was then separated byHPLC (toluene-ethylacetate 2:1) with recyling. The less polardiastereoisomer was recrystallized from ethyl ether giving 786 mg of[2S-[2beta(1R*,2R*)]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 2-hydroxy-1-methylpropyl ester, as a colorless solid, mp 94.5°-98°C.; [α]D²⁵ -7.99° (Cl, CHCl₃).

Analysis for C₂₁ H₂₉ BrO₆ : Calculated: C, 55.15; H, 6.39, Found: C,54.79; H, 6.20.

Recrystallization of the more polar diastereoisomer from ethyl ethergave 1.03 g of[2R-[2alpha(1R*,2R*)]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 2-hydroxy-1-methylpropyl ester (mp 80°-83° C.; [α]D²⁵ -21.49° (c1,CHCl₃)) as a colorless solid.

Analysis for C₂₁ H₂₉ BrO₆ : Calculated: C, 55.15; H, 6.39. Found: C,55.06; H, 6.39.

EXAMPLE 61

Using the procedure described in Example 26, 199.8 mg of[2S-(2beta(1R*,2R*)]]-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 2-hydroxy-1-methylpropyl ester was alkylated with2',4'-dihydroxy-3'-n-propylacetophenone. After chromatographicpurification on a silica gel column, 106 mg (42.8%) of[2S-(2beta(1R*,2R*)]]-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 2-hydroxy-1-methyl propyl ester was obtained [α]D²⁵ -7.25° (c1,CHCl₃); (mp 124°-127.5° C.) (recrystallized from ethyl acetate-hexane).

Analysis for C₃₂ H₄₂ O₉ : Calculated: C, 67.35; H, 7.42. Found: C,67.14; H, 7.51.

EXAMPLE 62

Using the procedure of example 61, 554 mg of the 2R-bromo ester fromexample 60 was converted into[2R-(2alpha(1R*,2R*)]-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid 2-hydroxy-1-methylpropyl ester in 72.6% yield (mp 100°-105° C.;[α]D²⁵ -15.75° (c1, CHCl₃); from ethyl acetate-hexane).

Analysis for C₃₂ H₄₂ O₉ : Calculated: C, 67.25; H, 7.42. Found: C,66.98; H, 7.39.

EXAMPLE 63

A 405 mg sample of the 2S-isomeric ester from example 61 was saponifiedwith lithium hydroxide monohydrate (0.6 g) in 10 ml of 1:1tetrahydrofuran-water using the procedure described in Example 4. Aftercrystallization from ethyl acetate-hexane, 185 mg (52.2%) of(S)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid, mp 94°-97.5° C. [α]D²⁵ +1.25° (c1, CHCl₃) was obtained.

Analysis for C₂₈ H₃₄ O₈ : Calculated: C, 67.45; H, 6.87. Found: C,66.60; H, 6.70.

EXAMPLE 64

Using the procedure of example 63, 502 mg of the 2R-isomeric ester fromexample 62 yielded, after crystallization from ethyl acetate hexane, 185mg (40.7%) of(R)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid, mp 102.5°-108° C., [α]D²⁵ -1.02° (c1, CHCl₃).

Analysis for C₂₈ H₃₄ O₈ : Calculated: C, 67.45; H, 6.87. Found: C,67.26; H, 6.78.

EXAMPLE 65

A mixture of 1 g (4.5 mmoles) ofracemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethylester, 3.7 ml (27.2 mmoles) of 1,5-dibromopentane, 2 g (14.5 mmoles) ofanhydrous potassium carbonate, 30 ml of acetone, and 15 ml ofN,N-dimethylformamide was stirred and refluxed for 20 hours. The mixturewas cooled and diluted with ether. The ether solution was washed withwater and saturated brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure giving 7.2 g of ayellow liquid. This material was chromatographed on 50 g of silica gel.Elution with 19:1 and 9:1 toluene-ethyl acetate afforded 1.2 g (72%) ofracemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester as a pale yellow oil.

EXAMPLE 66

Using the procedure and molar proportions of example 65, the followingcompounds were prepared from the indicated starting materials. Allcompounds were purified by chromatography on silica gel and wereisolated as pale yellow oils:

Racemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-7-hydroxy-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester and 1,5-dibromopentane.

Racemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acidethyl ester and 1,5-dibromohexane.

Racemic-6-acetyl-7-[(6-bromohexyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acidethyl ester and 1,6-dibromopentane.

Racemic-6-acetyl-7-[(4-bromobutyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acidethyl ester and 1,4-dibromobutane.

Racemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-3,4-dihydro-7-hydroxy-8-propyl-2H-1-benzopyran-2-carboxylic acidethyl ester and 1,5-dibromopentane.

Racemic-8-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid methyl ester fromracmic-8-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acidmethyl ester and 1,5-dibromopentane.

EXAMPLE 67

A mixture of 1.2 g (3.23 mmoles) ofracemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester, 1.0 g (5.15 mmoles) of2',4'-dihydroxy-3'-propylacetophenone, 1.8 g (13.0 mmoles) of anhydrouspotassium carbonate, 30 ml of acetone, and 15 ml ofN,N-dimethylformamide was stirred and refluxed for 6 hr. After beingcooled, the mixture was diluted with ether. The ether phase was washedwith water and brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue (2.1 g) waschromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethylacetate afforded 1.3 g (83%) ofracemic-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester as a yellow oil.

EXAMPLE 68

Using the procedure and molar proportions of example 67, the followingcompounds were prepared from the indicated starting materials. Allcompounds were purified by chromatography on silica gel and wereisolated as pale yellow oils:

Rac-6-acetyl-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxyacetophenone.

Rac-6-acetyl-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxyacetophenone.

Rac-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxy-3'-propylacetophenone.

Rac-7-[5-(4-Acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxyacetophenone.

Rac-6-acetyl-7-[6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-7-[(6-bromohexyl)oxy]-3,4-dihydro-2H-1-benzoyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxy-3'-propylacetophenone.

Rac-6-acetyl-7-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-6-acetyl-7-[(4-bromobutyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxy-3'-propylacetophenone.

Rac-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxy-acetophenone.

Rac-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydroxy-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester fromracemic-7-[(5-bromopentyl)oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylicacid ethyl ester and 2',4'-dihydroxy-3'-propylacetophenone.

Rac-8-acetyl-7-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid methyl ester fromracemic-8-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid methyl ester and 2',4'-dihydroxy-3'-propylacetophenone.

EXAMPLE 69

A mixture of 1.3 g (2.68 mmoles) of the ester product from example 67,60 ml of 1:1 tetrahydrofuran-water, and 2.4 g (57.1 mmoles) of lithiumhydroxide monohydrate was stirred at room temperature for 5 hours. Themixture was diluted with water and extracted three times with ether. Theaqueous phase was acidified to pH 1 with 2N HCl and extracted threetimes with ethylacetate. The ethyl acetate extracts were combined,washed with saturated brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate giving 0.725 g (59%) ofracemic-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid as a colorless solid, mp 124°-126.5° C.

Analysis Calculated for C₂₆ H₃₂ O₇ : C, 68.40; H, 7.07. Found C, 68.34;H, 7.29.

Using the procedure and molar proportions of example 69, the acids shownin the following table were prepared by saponification of thecorresponding ester from example 68:

    __________________________________________________________________________                                  Recryst.                                        Microanalysis                 mp °C.                                                                       from  Formula                                                                            Calc % C.H                                                                            Found %                __________________________________________________________________________                                                           C.H                    rac-6-acetyl-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-                                                    105-107                                                                             Ethyl C.sub.28 H.sub.34 O.sub.8                                                          67.45,6.87                                                                            67.24,6.91             3,4-dihydro-8-propyl-2H--1-benzopyran-2-carboxylic acid                                                           Acetate-                                                                      Hexane                                    rac-6-acetyl-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-                                                      183-185.5                                                                         Ethyl C.sub.25 H.sub.28 O.sub.8                                                          65.78,6.18                                                                            65.80,6.08             3,4-dihydro-2H--1-benzopyran-2-carboxylic acid                                                                    Acetate                                   rac-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)-                                                     oil   --    C.sub.31 H.sub.40 O.sub.8                                                          68.87,7.46                                                                            68.76,7.70             pentyloxy]-3,4-dihydro-8-propyl-2H--1-benzopyran-2-                           carboxylic acid                                                               rac-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-                                                         146.5-149                                                                           Ethyl C.sub.23 H.sub.26 O.sub.7                                                          66.65,6.32                                                                            66.51,6.29             dihydro-2H--1-benzopyran-2-carboxylic acid                                                                        Acetate-                                                                      Hexane                                    rac-6-acetyl-7-[6-(4-acetyl-3-hydroxy-2-propyl-                                                             138.5-142                                                                           Ethyl C.sub.29 H.sub.36 O.sub.8                                                          67.95,7.08                                                                            67.99,7.14             phenoxy)hexyloxy]-3,4-dihydro-2H--1-benzopyran-2-                                                                 Acetate-                                  carboxylic acid                     Hexane                                    rac-6-acetyl-7-[4-(4-acetyl-3-hydroxy-2-propyl-                                                             137-140                                                                             Ethyl C.sub.27 H.sub.32 O.sub.8                                                          66.93,6.66                                                                            67.21,6.77             phenoxy)butoxy]-3,4-dihydro-2H--1-benzopyran-2-                                                                   Acetate-                                  carboxylic acid                     Hexane                                    rac-7-[5-(4-acetyl-3-hydroxyphenoxy)pentyloxy]-3,4-                                                         120-123                                                                             Ethyl C.sub.26 H.sub.32 O.sub.7                                                          68.40,7.07                                                                            68.70,7.14             dihydro-8-propyl-2H--1-benzopyran-2-carboxylic acid                                                               Acetate-                                                                      Hexane                                    rac-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl-                                                        oil   --    C.sub.29 H.sub.38 O.sub.7                                                          69.86,7.68                                                                            70.02,7.80             oxy]-3,4-dihydro-8-propyl-2H-- -1-benzopyran-2-carboxylic                     acid                                                                          rac-8-acetyl-7-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)-                                                    134-136                                                                             Aceto-                                                                              C.sub.28 H.sub.34 O.sub.8                                                          67.45,6.87                                                                            67.20,6.84             pentyl]oxy]-3,4dihydro-2H--1-benzopyran-2-carboxylic acid                                                         nitrile                                   __________________________________________________________________________

EXAMPLE 71

A mixture of 6.5 g (24.6 mmoles) of(R)-(+)-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester, 10.37 g (75.1 mmoles) of anhydrous potassiumcarbonate, 1.12 g of 18-crown-6, 39.3 ml (0.2 mole) of1,5-dibromopentane, and 150 ml of acetonitrile was stirred and refluxedfor 21 hours. After being cooled, the mixture was treated with ether andwater. The organic layer was separated, washed with water and brine,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue (68 g) was purified first by columnchromatography on silica gel (400 g; eluting with 49:1 toluene-ethylacetate) and then by preparative HPLC on silica gel using 9:1hexane-ethyl acetate as the mobile phase. There was obtained 9.71 g(95.6%) of(R)-(+)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a solid. Recrystallization from ethanol gave acolorless solid mp 64°- 65.5° C., [α]D²⁵ +36.37° (c2, CHCl₃).

Analysis Calculated for C₂₀ H₂₉ BrO₄ : C, 58.12; H, 7.07; Br, 19.33.Found: C, 58.01; H, 7.07; Br, 19.20.

EXAMPLE 72

Using the procedure and molar proportions of example 71,(S)-(-)-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester was alkylated with 1,5-dibromopentane giving(S)-(-)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester, [α]D²⁵ -34.60° (c2, CHCl₃), in 88.5% yield.

Analysis Calculated for C₂₀ H₂₉ BrO₄ : C, 58.12; H, 7.07; Br 19.33.Found: C, 58.00; H, 7.19; Br, 19.33.

EXAMPLE 73

Using the procedure and molar proportions of example 71, 1 g ofracemic-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester was alkylated with 1,5-dibromopentane givingracemic-6-[(5-bromopentyl)-oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a colorless solid, mp 72.5°-74.5° C. in 90% yieldafter purification by chromatography on silica gel.

Analysis Calculated for C₂₀ H₂₉ BrO₄ : C, 58.12; H, 7.07; Br, 19.33.Found: C, 58.13; H, 7.15; Br, 19.30.

EXAMPLE 74

A mixture of 7.35 g (17.8 mmoles) of the (R)-(+)-bromo ester productfrom example 71, 3.85 g (19.8 mmoles) of2',4'-dihydroxy-3'-propylacetophenone, 8.93 g (64.7 mmoles) of anhydrouspotassium carbonates, 154 ml of dry acetone, and 77 ml of dryN,N-dimethylformamide was stirred and refluxed for 5.5 hr. The mixturewas cooled and diluted with ethyl acetate. The organic phase was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure giving 10.8 g of anoil. This material was purified by preparative HPLC on silica gel using2:1 hexane-ethyl acetate as the mobile phase. There was obtained 9.1 g(97%) of(R)-(+)-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester as a yellow oil, [α]D²⁵ +26.62° (c2, CHCl₃).

Analysis Calculated for C₃₁ H₄₂ O₇ : C, 70.70; H, 8.04. Found: C, 70.06;H, 8.18.

EXAMPLE 75

Using the procedure of example 74, the (S)-(-)-bromo ester product fromexample 72 (8.4 g) was converted by alkylation of2',4'-dihydroxy-3'-propylacetophenone (4.4 g) into(S)-(-)-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester in 91% yield. This material was a yellow oil.

Analysis Calculated for C₃₁ H₄₂ O₇ : C, 70.70; H, 8.04. Found: C, 70.13;H, 7.73.

EXAMPLE 76

Using the procedure and molar proportions described in example 74, 1.2 gof the racemic bromo ester product from example 73 was converted byalkylation of 2',4'-dihydroxy-3'-propylacetophenone (0.834 g) intoracemic6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid methyl ester in 72% yield, as a pale yellow oil.

Analysis Calculated for C₃₁ H₄₂ O₇ : C, 70.70; H, 8.04; Found: C, 70.44;H, 7.97.

EXAMPLE 77

A mixture of 7.55 g (14.3 mmoles) of the (R)-(+)-ester product fromexample 74, 140 ml of tetrahydrofuran, 90 ml of water, and 12.6 g (0.21mole) of lithium hydroxide monohydrate was stirred for 7 hours at roomtemperature and kept at 0° C. for 17 hr. The mixture was poured intocold 3N HCl. The organic materials were extracted three times with ethylacetate. The extracts were combined, washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The residual yellow glass (7.3 g) waschromatographed on 350 g of silica gel. Elution with 4:1, 2:1, and 1:1toluene-ethyl acetate gave the desired acid (5 g) which wasrecrystallized from acetonitrile. There was obtained 2.49 g (34%) of(R)-(+)-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid as a colorless solid, mp 92.5°-95° C., [α]D²⁵ +37.86° (c2, CHCl₃).

Analysis Calculated for C₃₀ H₄₀ O₇ : C, 70.29; H, 7.87. Found: C, 70.25;H, 7.92.

EXAMPLE 78

Using the procedure of example 77, 9.35 g (17.8 mmoles) of the(S)-(-)-ester product from example 75 was saponified.(S)-(-)-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid was obtained as a colorless solid, mp 90°-93.5° C. [α]D²⁵ -38.18°(c2, CHCl₃), after recrystallization from acetonitrile.

Analysis Calculated for C₃₀ H₄₀ O₇ : C, 70.29; H, 7.87. Found: C, 70.50;H, 8.11.

EXAMPLE 79

Using the procedure of example 77, 5.8 g (11 mmoles) of the racemicester from example 76 was saponified. There was obtained 2.77 g (49%) ofracemic-6-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylicacid as a colorless solid, mp 92.5°-95° C.

Analysis Calculated for C₃₀ H₄₀ O₇ : C, 70.29; H, 7.87. Found: C, 70,28;H, 7.98.

EXAMPLE 80

A mixture of 2 g (4 mmoles) ofracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid and 155 ml of water was treated with 40 ml (4 mmoles) of 0.1Naqueous sodium hydroxide solution. The mixture was stirred for 2 hoursat room temperature then filtered with suction. The filtrate wasfreeze-dried giving a solid residue which was dissolved in hot ethylacetate containing a small amount of ethanol. Hexane was added and aprecipitate resulted. The mixture was stored at 0° C. overnight thenfiltered with suction. The solid was washed with ethyl acetate-hexane(2:1) and the recrystallization procedure was repeated. After dryingunder high vacuum at 60° C., there was obtained 1.6 g (77%) of themonosodium salt of the starting acid as a colorless solid.

Analysis Calculated for C₂₈ H₃₃ NaO₈ : C, 64.61; H, 6.39; Na, 4.42.Found: C, 64.50; H, 6.55; Na, 4.17.

EXAMPLE 81

To a solution of 2 g (4 mmoles) ofracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid in 15 ml of ethanol was added a solution of 0.242 g (2 mmoles) ofd-(+)-α-methylbenzylamine in 4 ml of ether. The resulting solution wasdiluted with 10 ml of ether and stored at 0° C. The precipitate wasfiltered with suction and washed with ether. Recrystallization fromethanol gave 0.742 g (60%) of a colorless solid, mp 167°-170° C. whichwas mainly the d-amine salt of the (S)-acid. This salt was suspended inethyl acetate and shaken with 1N HCl. The organic layer was separated,washed with water, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. There was obtained 0.58 g of(S)-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid as a solid. A sample of this material was esterified withdiazomethane. The resulting methyl ester was analyzed for enantiomericcomposition by liquid chromatography on a 30 cm Pirkle covalentphenylglycine column. This analysis revealed that the acid obtained bythis resolution procedure was composed of 95.3% of the (S)-enantiomer(less polar methyl ester) and 4.7% of the (R)-enantiomer (more polarmethyl ester).

EXAMPLE 82

A mixture of 6 g (27 mmoles) ofracemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethylester, 6.8 g (54 mmoles) of benzyl chloride, 7.5 g (54 mmoles) ofanhydrous potassium carbonate, and 4.5 g (27 mmoles) of potassium iodidein 100 ml of acetone was stirred and refuxed for 7 hr. Most of theacetone was removed under reduced pressure and the residue was dilutedwith ethyl acetate. The organic phase was washed with water, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure giving 17.4 g of a yellow oil. This material waschromatographed on silica gel. Elution with 19:1 toluene-ethyl acetateafforded 6.9 g (78%) ofracemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-carboxylic acidethyl ester as a yellow oil.

EXAMPLE 83

The ether ester product from example 82 (6.9 g, 22 mmoles) was dissolvedin 70 ml of toluene and the solution was cooled to -78° C.(dry-ice-acetone bath). With stirring, 15.6 ml of a 25% solution ofdiisobutylaluminum hydride in toluene was added dropwise. The reactionmixture was stirred at -78° C. for 2 hours whereupon 2.5 ml of methanolwas cautiously added followed by 2N HCl and ice. The mixture wasextracted with ethyl acetate and the organic extracts were combined,washed with saturated brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue (7.6 g)was chromatographed on silica gel. Elution with 9:1 toluene-ethylacetate gave 5.6 g (70%) ofracemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-carboxaldehydeas a pale yellow oil.

EXAMPLE 84

Using the procedure of example 30, 2.7 g (10 mmoles) of the aldehydeproduct from example 83 was condensed with 3.7 g (10.6 mmoles) of(carbethoxymethylene)triphenylphosphorane, in 30 ml of toluene (1.5hours at 100° C.). After chromatography of the crude product on 50 g ofsilica gel (eluting with toluene), there was obtained 3.0 g (88.8%) ofracemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-propenoic acidethyl ester (mixture of E- and Z-isomers), as a pale-yellow oil.

EXAMPLE 85

The propenoic ester product from example 84 (3 g; 8.9 mmoles) washydrogenated at atmospheric pressure and room temperature, over 0.3 g of10% palladium on carbon, in ethyl acetate (35 ml), giving 2.4 g ofracemic-3,4-dihydro-7-hydroxy-2H-1-propanoic acid ethyl ester as aviscous oil, after filtration of the catalyst and solvent evaporation.

EXAMPLE 86

Using the procedure of example 41, the propanoic ester product fromexample 85 was converted into 1.4 g (54%) ofracemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-propanoic acidethyl ester, a yellow oil which crystallized on standing, obtained afterchromatography on silica gel (eluting with 19:1 toluene-ethyl acetate).

EXAMPLE 87

Using the procedure of example 65, the acetyl propanoic ester productfrom example 86 (1.4 g, 4.79 mmoles) was converted intoracemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-propanoicacid ethyl ester in 76% yield (1.6 g) as a yellow oil which crystallizedon standing (purified by chromatography on silica gel, eluting with 19:1toluene-ethyl acetate).

EXAMPLE 88

Using the procedure of example 67, the bromoester product from example87 (1.6 g; 3.63 mmoles) was converted intoracemic-6-acetyl-7-[(5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-propanoicacid ethyl ester by alkylation of 2',4'-dihydroxy-3'-propylacetophenone.After purification by chromatography on silica gel (eluting with 9:1 and4:1 toluene-ethyl acetate), the ester product was obtained in 79% yield(1.6 g) as a pale-yellow oil.

EXAMPLE 89

Using the procedure of example 69, the ester product from example 88(1.6 g; 2.89 mmoles) was saponified giving 1 g (66%) ofracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-propanoicacid as a colorless solid mp 126.5°-129° C. after recrystallization fromethyl acetate-hexane and then acetonitrile.

Analysis Calculated for C₃₀ H₃₈ O₈ : C, 68.42; H, 7.27. Found: C, 68.42;H, 7.49.

EXAMPLE 90

Using the procedure of example 30, 2.7 g (10 mmoles) of the aldehydeproduct from example 83 was condensed with 4.4 g (12 mmoles) of ethyl4(triphenylphosphoranylidene)-2-butenoate in 30 ml of toluene (3.5 hr at100° C.). Chromatography of the crude product of 100 g of silica gelgave 1.1 g (30%) ofracemic-5-[3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-yl]-2,4-pentadienoicacid ethyl ester (mixture of E- and Z-isomers) as a yellow oil elutedwith toluene and 19:1 toluene-ethyl acetate.

EXAMPLE 91

The dienoic ester product from example 90 (1.1 g; 3.02 mmoles) washydrogenated at atmospheric pressure and room temperature, in 15 ml ofethyl acetate, over 0.95 g of 10% palladium on carbon. The catalyst wasfiltered and the filtrate was concentrated under reduced pressure giving0.9 g (100%) ofracemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-pentanoic acid ethylester as a pale-yellow oil.

EXAMPLE 92

Using the procedure of example 41, the pentanoic ester product fromexample 91 was converted intoracemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-pentanoic acidethyl ester (0.4 g; 41%) as a yellow oil which crystallized on standing.

EXAMPLE 93

Using the procedure of example 65, the acetyl pentanoic ester fromexample 92 (0.4 g; 1.25 mmoles) was converted intoracemic-6-acetyl-7-[(5-bromopentyl)oxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid ethyl ester as a yelow oil obtained in 51% yield (0.3 g) aftercolumn chromatography on silica gel (eluting with 19:1 toluene-ethylacetate).

EXAMPLE 94

Using the procedure of example 67, the bromo ester product from example93 (0.3 g; 0.64 mmole) was converted intoracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid ethyl ester by alkylation of 2',4'-dihydroxy-3'-propylacetophenone.After purification by chromatography on silica gel (eluting with 19:1toluene-ethyl acetate), the ester product was obtained in 80% yield (0.3g) as a yellow oil.

EXAMPLE 95

Using the procedure of example 69, the ester product from example 94(0.3 g, 0.51 mmoles) was saponified giving 0.137 g (48%) ofracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid as a colorless solid, mp 116°-120.5° C., after recrystallizationfrom acetonitrile.

Analysis Calculated for C₃₂ H₄₂ O₈ : C, 69.29; H, 7.63. Found: C, 69.35;H, 7.66.

EXAMPLE 96 Aerosol Formulation (Freon Suspension Aerosol)

    ______________________________________                                                        mg/100 μl                                                  Ingredients       1      mg    10   mg  25   mg                               ______________________________________                                        racemic-6-acetyl-7-                                                                             1      mg    10   mg  25   mg                               [5-(4-acetyl-3-hydroxy-                                                       2-propylphenoxy)-                                                             pentyloxy]-3,4-dihydro-                                                       2H--1-benzopyran-2-                                                           carboxylic acid                                                               (micronized)                                                                  Glyceryl Trioleate                                                                              0.03   mg    3.0  mg  7.5  mg                                Freon 114* 30 parts                                                                              To                                                                                  100  μl                                                                             100  μl                                                                             100  μl                        Freon 12 70 parts  Make                                                       ______________________________________                                         *Freon 11 can be substituted.                                            

Procedure:

Micronizeracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid to the 1-10 micron particle range by air attrition and place in anappropriate container. Add glyceryl trioleate at room temperature. Chillthe Freon to -30° C. and then add it to mixture. Seal a preciseappropriate volumetric valve into the container immediately after addingthe Freon and place the container in an ultrasonic generator to dispersetheracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid in the Freon.

EXAMPLE 97 Aerosol Formulation (Sodium Salt Freon Suspension Aerosol)

    ______________________________________                                                        mg/100 μl                                                  Ingredients       1 mg     10 mg    25 mg                                     ______________________________________                                        Sodium Salt of racemic-6-                                                                       1 mg     10 mg    25 mg                                     acetyl-7-[5-(4-acetyl-3-                                                      hydroxy-2-propylphenoxy)-                                                     pentyloxy]-3,4-dihydro-                                                       2H--1-benzopyran-2-                                                           carboxylic acid (micronized)                                                  Oleic Acid        0.01 to  1.0 mg to                                                                              3.0 mg to                                                   0.03 mg  3.0 mg   7.5 mg                                     Freon 114*                                                                            30 parts       To                                                                                100 μl                                                                            100 μl                                                                            100 μl                           Freon 12                                                                              70 parts       Make                                                   ______________________________________                                         *Freon 11 can be substituted.                                            

Procedure:

Micronize the sodium salt ofracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid to the 1-10 micron particle range by air attrition and place in anappropriate container. Add glyceryl trioleate at room temperature. Chillthe Freon to -30° C. and then add it to mixture. Seal a preciseappropriate volumetric valve onto the container immediately after addingthe Freon and place the container in an ultrasonic generator to dispersethe sodium salt ofracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydroxy-2H-1-benzopyran-2-carboxylicacid in the Freon.

EXAMPLE 98 Aerosol Formulation (Freon Solution Aerosol)

    ______________________________________                                                    mg/100 μl                                                      Ingredients   1.0     mg     10.0 mg  25.0  mg                                ______________________________________                                        racemic-6-acetyl-7-                                                                         1.0     mg     10.0 mg  25.0  mg                                [5-(4-acetyl-3-hydroxy-                                                       2-propylphenoxy)-                                                             pentyloxy]-3,4-dihydro-                                                       2H--1-benzopyran-2-                                                           carboxylic acid                                                               Dimethylsulfoxide                                                                           3.0     μl  10.0 μl                                                                             20.0  μl                             Ethanol 99.9  6.0     μl  6.0  μl                                                                             6.0   μl                             Methylene Chloride                                                                          10      μl  10   μl                                                                             10    μl                             Freon 12 To Make                                                                            100     μl  100  μl                                                                             100   μl                             ______________________________________                                    

Procedure:

Dissolveracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid in dimethylsulfoxide at room temperature in an appropriatecontainer. Add the ethanol and methylene chloride to the mixture. Thenadd the Freon which has been chilled to -30° C. Seal a preciseappropriate volumetric valve onto the container immediately after addingthe Freon.

EXAMPLE 99 Aerosol Formulation (Freon Solution Aerosol)

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        racemic-6-acetyl-7-[5-(4-acetyl-                                                                   50.0       mg                                            3-hydroxy-2-propylphenoxy)-                                                   pentyloxy]-3,4-dihydro-2H--1-                                                 benzopyran-2-carboxylic acid                                                  Dimethylsulfoxide    150        μl                                         Ethanol 99.9%        0.3        ml                                            Methylene Chloride   0.5        ml                                            Freon 12             4.2        ml                                            Total Volume         5.0        ml                                            Concentration of Active Ingredient                                                                 1 mg/0.1 ml                                              ______________________________________                                    

Procedure: The same procedure as in Example 98 was employed in thisExample.

EXAMPLE 100 Nebulization Formulation (Solution for Nebulization)

    ______________________________________                                                        mg/ml                                                         Ingredients       25.0   mg    50.0 mg  100.0                                                                              mg                               ______________________________________                                        racemic-6-acetyl-7-[5-(4-                                                                       25.0   mg    50.0 mg  100.0                                                                              mg                               acetyl-3-hydroxy-2-                                                           propylphenoxy)pentyloxy]-                                                     3,4-dihydro-2H--1-benzopyran-                                                 2-carboxylic acid                                                             Phosphate Buffer  1.0    ml    1.0  ml  1.0  ml                               Containing Sodium                                                             Hydroxide to pH 7.8 To Make                                                   ______________________________________                                    

Procedure:

Dissolveracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylicacid into the phosphate buffer containing an equimolar amount of sodiumhydroxide resulting in a solution having a pH of 7.8.

EXAMPLE 101 Capsule Formulation

    ______________________________________                                                       mg/capsule                                                     Ingredients      25 mg   50 mg   100 mg                                                                              200 mg                                 ______________________________________                                        racemic-6-acetyl-7-[5-(4-                                                                       25      50     100   200                                    acetyl-3-hydroxy-2-propyl-                                                    phenoxy)pentyloxy]-3,4-di-                                                    hydro-2H--1-benzopyran-2-                                                     pentanoic acid                                                                Lactose          375     155     200   140                                    Starch            30      30      35    40                                    Talc              20      15      15    20                                    Weight of        450 mg  250 mg  350 mg                                                                              400 mg                                 capsule                                                                       ______________________________________                                    

Procedure:

Millracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid, lactose and starch in a suitable mixer. Mill. Add talc and mixwell. Encapsulate on suitable equipment.

EXAMPLE 102 Tablet Formulation (Wet granulation)

    ______________________________________                                                       mg/tablet                                                      Ingredients      25 mg   50 mg   100 mg                                                                              200 mg                                 ______________________________________                                        racemic-6-acetyl-7-[5-(4-                                                                       25      50     100   200                                    acetyl-3-hydroxy-2-propyl-                                                    phenoxy)pentyloxy]-3,4-di-                                                    hydro-2H--1-benzopyran-2-                                                     pentanoic acid                                                                Lactose          280     153     187   171                                    Modified Starch   55      25      35    45                                    Pregelatinized    35      20      25    30                                    Starch                                                                        Distilled        --      --      --    --                                     water q.s.                                                                    Magnesium         5       2       3     4                                     Stearate                                                                      Weight of        400 mg  250 mg  350 mg                                                                              450 mg                                 tablet                                                                        ______________________________________                                    

Procedure:

Mixracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-banzopyran-2-pentanoicacid, lactose, modified starch and pregelatinized starch in a suitablemixer. Granulate with sufficient distilled water to proper consistency.Mill. Dry in a suitable oven. Mill and mix with magnesium stearate for 3minutes. Compress on a suitable press equipped with appropriatedpunches.

EXAMPLE 103 Tablet Formulation (Direction Compression)

    ______________________________________                                                            mg/tablet                                                 Ingredients         25 mg                                                     ______________________________________                                        racemic-6-acetyl-7-[5-(4-                                                                         25                                                        acetyl-3-hydroxy-2-propyl-                                                    phenoxy)pentyloxy]-3,4-di-                                                    hydro-2H--1-benzopyran-2-                                                     pentanoic acid                                                                Lactose             181                                                       Avicel              55                                                        Direct Compression Starch                                                                         35                                                        Magnesium Stearate  4                                                         Weight of tablet    300        mg                                             ______________________________________                                    

Procedure:

Millracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid with an equal amount of lactose. Mix well. Mix with avicel anddirect compression starch, and the remaining amount of lactose. Mixwell. Add magnesium stearate and mix for 3 minutes. Compression on asuitable press equipped with appropriate punches.

We claim:
 1. A compound of the formula ##STR21## wherein R₁ is hydrogenor lower alkyl; R² is hydrogen or halogen, R³, R⁴ and R⁵, independently,are hydrogen, alkanoyl, benzoyl or lower alkyl; R⁶ and R⁷,independently, are hydrogen or lower alkyl; X is alkylene of 3 to 7carbon atoms; and n is as an integer of one to four provided one of R³,R⁴ or R⁵ is alkanoyl or benzoyl and the other two, independently, arehydrogen or lower alkyl; oran enantiomer thereof, or, when R⁷ ishydrogen, a salt thereof, with a pharmaceutically acceptable base.
 2. Acompound, in accordance with claim 1, wherein R¹ is lower alkyl, R² ishydrogen, R³ is alkanoyl or benzoyl, and R⁴, R⁵, R⁶ and R⁷ are hydrogen.3. A compound, in accordance with claim 2, wherein X is alkylene of 3 to5 carbon atoms.
 4. A compound, in accordance with claim 3, wherein R³ isacetyl.
 5. A compound, in accordance with claim 4, wherein R¹ is propyl.6. A compound, in accordance with claim 1,racemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy3,4-dihydro]-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid.
 7. A compound, in accordance with claim 1,racemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid.
 8. A pharmaceutical composition having SRS-A antagonisticactivity, comprising an effective amount of a compound of the formula##STR22## wherein R₁ is hydrogen or lower alkyl; R² is hydrogen orhalogen; R³, R⁴ and R⁵, independently, are hydrogen, alkanoyl, benzoylor lower alkyl; R⁶ and R⁷, independently, are hydrogen or lower alkyl; Xis alkylene of 3 to 7 carbon atoms; and n is an integer of one to four;provided that one of R³, R⁴ or R⁵ is alkanoyl or benzoyl and the othertwo, independently, are hydrogen or lower alkyl; oran enantiomerthereof, or, when R⁷ is hydrogen, a salt thereof, with apharmaceutically acceptable base, and an inert carrier material.
 9. Acomposition in accordance with claim 8, wherein the compound of formulaI isracemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid.
 10. A composition in accordance with claim 8, wherein the compoundof formula I isracemic-6-acetyl-7-[5-(4-acetyl-hydroxy-2-propylphenoxy)pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid.
 11. A method of treating allergic conditions requiring SRS-Aantagonistic activity, which comprises administering an effective amountof a compound of the formula ##STR23## wherein R₁ is hydrogen or loweralkyl; R² is hydrogen or halogen; R³, R⁴ and R⁵, independently, arehydrogen, alkanoyl, benzoyl or lower alkyl; R⁶ and R⁷, independently,are hydrogen or lower alkyl; X is alkylene of 3 to 7 carbon atoms; and nis an integer of one to four; provided that one of R³, R⁴ or R⁵ isalkanoyl or benzoyl and the other two, independently, are hydrogen orlower alkyl; oran enantiomer thereof, or, when R⁷ is hydrogen, a saltthereof, with a pharmaceutically acceptable base.
 12. A method inaccordance with claim 11, wherein the compound of formula I isracemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoicacid.
 13. A method in accordance with claim 11, wherein the compound offormula I isracemic-6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy]-3,4-dihydro-2H-1-benzopyran-2-pentanoicacid.